HIV integrase inhibitors

ABSTRACT

The present invention relates to the inhibition of HIV integrase, and to the treatment of AIDS or ARC by administering compounds of the formula  
                 
 
     wherein R 1  is C 1 -C 4  alkyl, carbocyclic radical, heterocyclic radical, aryl-C 1 -C 2  alkylene, aryloxy-C 1 -C 2  alkylene, alkoxy-CC(O)—, wherein R 1  is optionally substituted from 1-3 times with halo, C 1 -C 2  alkyl or C 1 -C 2  alkoxy, or R 1  is H; R 2  is H or C 1 -C 4  alkyl; R 3  is H, C 1 -C 4  alkyl or phenyl-C 0 -C 2  alkylene which is optionally substituted with 1-3 R 5 ; R 4a  is carbocylic radical, heterocyclic radical, aryloxy, aryl-C 1 -C 4  alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R 4a  is optionally substituted with 1-3 R 5 ; and wherein each R 5  is independently selected from H, halo, C 1 -C 4  alkyl, C 1 -C 4  alkenyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxy, R 6 -phenyl, R 6 -phenoxy, R 6 -benzyl, R 6 -benzyloxy, NH 2 C (O)—, alkyl-NHC(O)—, wherein R 6  is H, halo; Z is a bond or a substituted or unsubstituted C 1 -C 4  alkylene group; and B 2  is

RELATED APPLICATIONS

[0001] This is a non-provisional application which claims the benefit of U.S. Provisional Application No. 60/211,900 filed Jun. 16, 2000.

BACKGROUND

[0002] Human immunodeficiency virus (HIV) has been identified as the etiological agent responsible for acquired immune deficiency syndrome (AIDS), a fatal disease characterized by destruction of the immune system and the inability to fight off life threatening opportunistic infections. Recent statistics (UNAIDS: Report on the Global HIV/AIDS Epidemic, December 1998), indicate that as many as 33 million people worldwide are infected with the virus. In addition to the large number of individuals already infected, the virus continues to spread. Estimates from 1998 point to close to 6 million new infections in that year alone. In the same year there were approximately 2.5 million deaths associated with HIV and AIDS.

[0003] There are currently a number of antiviral drugs available to combat the infection. These drugs can be divided into three classes based on the viral protein they target and their mode of action. In particular, saquinavir, indinavir, ritonavir, nelfinavir and amprenavir are competitive inhibitors of the aspartyl protease expressed by HIV. Zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavir are nucleoside reverse transcriptase inhibitors that behave as substrate mimics to halt viral cDNA synthesis. The non-nucleoside reverse transcriptase inhibitors, nevaripine, delavamidine and efavirenz inhibit the synthesis of viral cDNA via a non-competitive (or uncompetitive) mechanism. Used alone these drugs are effective in reducing viral replication. The effect is only temporary as the virus readily develops resistance to all known agents. However, combination therapy has proven very effective at both reducing virus and suppressing the emergence of resistance in a number of patients. In the US, where combination therapy is widely available, the number of HIV-related deaths has declined (Palella, F. J.; Delany, K. M.; Moorman, A. C.; Loveless, M. O.; Further, J.; Satten, G. A.; Aschman, D. J.; Holmberg, S. D. N. Engl. J. Med. 1998, 338, 853).

[0004] Unfortunately, not all patients are responsive and a large number fail this therapy. In fact, approximately 30-50% of patients ultimately fail combination therapy. Treatment failure in most cases is caused by the emergence of viral resistance. Viral resistance in turn is caused by the rapid turnover of HIV-1 during the course of infection combined with a high viral mutation rate. Under these circumstances incomplete viral suppression caused by insufficient drug potency, poor compliance to the complicated drug regiment as well as intrinsic-pharmacological barriers to exposure provides fertile ground for resistance to emerge. More disturbing are recent findings which suggest that low-level replication continues even when viral plasma levels have dropped below detectable levels (<50 copies/ml) (Carpenter, C. C. J.; Cooper, D. A.; Fischl, M. A.; Gatell, J. M.; Gazzard, B. G.; Hammer, S. M.; Hirsch, M. S.; Jacobsen, D. M.; Katzenstein, D. A.; Montaner, J. S. G.; Richman, D. D.; Saag, M. S.; Schecter, M.; Schoolery, R. T.; Thompson, M. A.; Vella, S.; Yeni, P. G.; Volberding, P. A. JAMA 2000, 283, 381). Clearly there is a need for new antiviral agents, preferably targeting other viral enzymes to reduce the rate of resistance and suppress viral replication even further.

[0005] HIV expresses three enzymes, reverse transcriptase, an apartyl protease and integrase, all of which are potential antiviral targets for the development of drugs for the treatment of AIDS. However, integrase stands out as being the only viral enzyme not targeted by current therapy. The integrase enzyme is responsible for insertion of the viral cDNA into the host cell genome, which is critical step in the viral life cycle. There are a number of discrete steps involved in this process including processing of the viral cDNA by removal of two bases from each 3′-terminus and joining of the recessed ends to the host DNA. Studies have shown that in the absence of a functional integrase enzyme HIV is not infectious. Therefore, an inhibitor of integrase would be useful as a therapy for AIDS and HIV infection.

[0006] A number of inhibitors of the enzyme have been reported. These include, nucleotide-based inhibitors, known DNA binders, catechols and hydrazide containing derivatives (Nemati, N.; Sundar, S.; Pommier, Y., Drug Disc. Today, 1997, 2, 487). However, no clinically active compound has resulted from these leads.

[0007] Thus, what is needed is a clinically effective inhibitor of the HIV integrase enzyme.

SUMMARY OF THE INVENTION

[0008] The present invention relates to compounds of Formula I, or pharmaceutically acceptable salts or solvates thereof.

[0009] In Formula I,

[0010] R¹ is C₁-C₄ alkyl, carbocyclic radical, heterocyclic radical, aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—, wherein R¹ is optionally substituted from 1-3 times with halo, C₁-C₂ alkyl or C₁-C₂ alkoxy, or R¹ is H;

[0011] R² is H or C₁-C₄ alkyl;

[0012] R³ is H, C₁-C₄ alkyl or phenyl-C₀-C₂ alkylene which is optionally substituted with 1-3 R⁵;

[0013] R⁴ is carbocylic radical, heterocyclic radical, aryloxy, aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R⁴ is optionally substituted with 1-3 R⁵, provided that, when R¹, R² and R³ are each H, R4 is not unsubstituted phenyl, o-methoxy phenyl or naphthalen-1-yl;

[0014] each R⁵ is independently selected from H, halo, C₁-C₄ alkyl, C₁-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl, R⁶-phenoxy, R⁶-benzyl, R⁶-benzyloxy, NH₂C(O)—, alkyl-NHC(O)—, wherein R⁶ is H, halo,

[0015] Z is a bond or a substituted or unsubstituted C₁-C₄ alkylene group;

[0016] B¹ is selected from the group consisting of

[0017] R⁷ is H or C₁-C₄ alkyl.

[0018] The present invention also relates to a method of inhibiting HIV integrase by administering to a patient an effective amount of a compound of Structural Formula Ia, or a pharmaceutically salt, solvate or prodrug thereof.

[0019] In Formula Ia, Z, R¹, R², R³, R⁵, R⁶ and R⁷ are as defined for Formula I, whereas R^(4a) is carbocylic radical, heterocyclic radical, aryloxy, aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R^(4a) is optionally substituted with 1-3 R⁵; and wherein B² is

[0020] The present invention further relates to a method of treating a patients infected by the HIV virus, or of treating AIDS or ARC, by administering to the patient an effective amount of a compound of Structural Formula Ia, or a pharmaceutically salt, solvate or prodrug thereof.

[0021] Another embodiment includes a pharmaceutical composition, useful for inhibiting HIV integrase, or for treating patients infected with the HIV virus, or suffering from AIDS or ARC, which comprises a therapeutically effective amount of one or more of the compounds of Formula Ia, including pharmaceutically acceptable salts, solvates or prodrugs thereof, and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

[0022] In the present invention, unless otherwise specified the following definitions apply.

[0023] The numbers in the subscript after the symbol “C” define the number of carbon atoms a particular group can contain. For example, “C₁-C₆” means a substituent containing from one to six carbon atoms.

[0024] As used herein, the term “alkyl” means a saturated, straight chain or branched monovalent hydrocarbon radical having the stated number of carbon atoms. Examples of such alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl and, where indicated, higher homologs and isomers such as n-pentyl, n-hexyl, 2-methylpentyl and the like. Haloalkyl refers to an alkyl radical that is substituted with one or more halo radicals, such as trifluoromethyl.

[0025] The term “alkenyl” means a partially-saturated, straight chain or branched monovalent hydrocarbon radical having the stated number of carbon atoms and is typified by groups such as vinyl, crotonyl and isopentyl.

[0026] The term “alkylene” means a bivalent straight chain alkyl radical having the stated number of carbon atoms such as methylene, 1,2-ethanediyl, 1,3-propanediyl and 1,4-butanediyl.

[0027] A preferred substituent for Z, when Z is a substituted C₁-C₄ alkylene group, is a hydroxyl group.

[0028] The term “alkoxy” means any of methoxy, ethoxy, n-propoxy, isopropoxy and the like.

[0029] “Halo” means chloro, bromo, iodo or fluoro radicals.

[0030] The term “carbocyclic radical” refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, 3-16 membered organic nucleus whose ring forming atoms are solely carbon atoms. Typical carbocyclic radicals include aryl, and fused carbocylic ring systems.

[0031] “Aryl” means aromatic hydrocarbon having from six to ten carbon atoms; examples include phenyl and naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl.

[0032] “Fused carbocyclic ring system” means an aromatic or non-aromatic, 5-8 membered ring which is optionally fused with one or more 5-6 membered rings. These fused 5-6 membered rings include aromatic groups, such as phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl, and non-aromatic rings such as cyclopentyl, cyclohexyl and cycloheptyl. Fused ring systems include, for example, dibenzoannulene, naphthylene, tetrahydronaphthylene and indanylene.

[0033] The term “heterocyclic radical” refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, heterocyclic nuclei having 5-16 ring atoms and containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur. Typical heterocyclic radicals include heteroaryl, heterocycloalkyl and fused heterocylic ring systems.

[0034] “Heteroaryl” means a five- or six-membered aromatic ring containing at least one and up to four non-carbon atoms selected from oxygen, sulfur and nitrogen. Examples of heteroaryl, as defined for R₁, include 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, 2-thienyl, 3-thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, 1,3,5-triazinyl and 1,3,5-trithianyl. Examples of a heteroaryl group, as defined for R₄, include thienyl, thiazolyl, pyradazinyl, pyrimidinyl, pyrrolyl and oxazolyl.

[0035] In a preferred embodiment, examples of a heteroaryl group, as defined for R₁, include 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and pyrazinyl.

[0036] “Fused heterocyclic ring system” means an aromatic or non-aromatic, 5-8 membered ring which is optionally fused with one or more 5-6 membered rings. These fused 5-6 membered rings include aromatic groups, such as phenyl, 1-napthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl, and non-aromatic rings such as cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, pyrrolyl and tetrahydofuryl. Examples of fused ring systems include: benzo[1,3]dioxolyl, benzo[b]thiophenyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0037] In a preferred embodiment, compounds of the present invention that are useful in treating AIDS have the structure of Formula II, shown below.

[0038] In Formula II, R¹, R², R³, R⁴, R⁵, R⁶ and Z are as defined for Formula I while B² is as defined in Formula Ia.

[0039] In yet another embodiment of the present inventions, compounds having the structure of Formula III, as follows, are preferred chemical intermediates from which compounds, or pharmaceutically acceptable salts, solvates or prodrugs, useful for the treatment of AIDS are formed. Even more preferentially, the compounds of Formula III are useful, themselves, as prodrugs and can be administered as a prodrug to a patient as a compound or in a pharmaceutical formulation.

[0040] In Formula III, R¹,R²,R³, R^(4a), R⁵,R⁶ and Z are as defined for Formula Ia.

[0041] In a more preferred embodiment, compounds-of the present invention have the structure of Formula V, shown below.

[0042] wherein:

[0043] W¹ is a bond or a C₁-C₄ alkylene group;

[0044] R¹¹ is aryl, aryloxy, aryl-cyclopropylene, heteroaryl, heteroaryloxy, wherein R¹¹ is optionally substituted from 1-3 times with halo, C₁-C₂ alkyl or C₁-C₂ alkoxy, or wherein R¹¹ is H;

[0045] Y¹ is a bond, C₁-C₃ alkylene or —O—C₁-C₂ alkylene; each R¹³ is independently selected from H, halo, N₂O, C₁-C₄ alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkyl, phenyl, phenoxy, benzyl, benzyloxy, p-halophenyl, p-halobenzyl, p-halophenoxy and p-halobenzyloxy; and B² is as defined in for Formula Ia.

[0046] In an even more preferred embodiment, compounds of the present invention have the structure of Formula VI, shown below.

[0047] wherein:

[0048] W² is C₁-C₃ alkylene;

[0049] R¹¹ is aryl, aryloxy, aryl-cyclopropylene, heteroaryl, heteroaryloxy, wherein R¹¹ is optionally substituted from 1-3 times with halo, C₁-C₂ alkyl or C₁-C₂ alkoxy, or R¹¹ is H;

[0050] Y² is a bond, C₁-C₃ alkylene;

[0051] each R¹⁴ is independently selected from H, halo, C₁-C₂ alkyl C₁-C₂ alkoxy, C₁-C₂ haloalkyl; and B² is as defined for Formula Ia.

[0052] In an alternate embodiment, compounds of the present invention have the structure of Formula VII, shown below.

[0053] wherein:

[0054] each Q is a bond or a methylene group;

[0055] each R¹⁵ is independently selected from H, halo, NO₂, C₁-C₄ alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkyl and CONHCH₃;

[0056] R¹⁶ is H or C₁-C₂ alkyl; and B² is as defined for Formula Ia.

[0057] By virtue of its acidic moiety, where applicable, a compound of Formula I forms salts by the addition of a pharmaceutically acceptable base. Such base addition salts include those derived from inorganic bases which include, for example, alkali metal salts (e.g. sodium and potassium), alkaline earth metal salts (e.g. calcium and magnesium), aluminum salts and ammonium salts. In addition, suitable base addition salts include salts of physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N′-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine, dehydroabietylamine, N,N′-bishydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, ethylenediamine, ornithine, choline, N,N′-benzylphenethylamine, chloroprocaine, diethanolamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane and tetramethylammonium hydroxide and basic amino acids such as lysine, arginine and N-methylglutamine. These salts may be prepared by methods known to those skilled in the art.

[0058] Salts of an amine group may also comprise quaternary ammonium salts in which the amino nitrogen carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.

[0059] Compounds of Formula I, which are substituted with a basic group, may exist as salts formed through acid addition. The acid addition salts are formed from a compound of Formula I and a pharmaceutically acceptable inorganic acid, including but not limited to hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, or organic acid such as p-toluenesulfonic, methanesulfonic, acetic, benzoic, citric, malonic, fumaric, maleic, oxalic, succinic, sulfamic, or tartaric. Thus, examples of such pharmaceutically acceptable salts include chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, citrate, acetate, malonate, fumarate, sulfamate, and tartrate.

[0060] Certain compounds of Formula I, and their salts, may also exist in the form of solvates with water, for example hydrates, or with organic solvents such as methanol, ethanol or acetonitrile to form, respectively, a methanolate, ethanolate or acetonitrilate. The present invention includes each solvate and mixtures thereof.

[0061] This invention also encompasses pharmaceutically acceptable prodrugs of the compounds of Formula I. Prodrugs are derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become, by solvolysis or under physiological conditions, the compounds of the invention which are pharmaceutically active in vivo.

[0062] A prodrug of a compound of Formula Ia may be formed in a conventional manner with a functional group of the compounds such as with an amino, hydroxy or carboxy group. The prodrug derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or (alkoxycarbonyl)oxy)alkyl esters. Examples of prodrugs of compounds of the present invention include the compounds described in Examples 143-146 as well as the ester chemical intermediates from which the compounds of Examples 1-57 were formed.

[0063] In a preferred embodiment, the prodrugs of the present invention comprise compounds of Formula III, examples of which are further provided in the exemplification.

[0064] In addition, a compound of Structural Formula I, or a salt, solvate or prodrug thereof, may exhibit polymorphism. The present invention also encompasses any such polymorphic form.

[0065] Certain compounds of Structural Formula I may contain one or more chiral centers and exist in different optically active forms. When compounds of Structural Formula I contain one chiral center, the compounds exist in two enantiomeric forms. The present invention includes both enantiomers and mixtures of enantiomers such as racemic mixtures. The enantiomers may be resolved by methods known to those skilled in the art, for example, by formation of diastereoisomeric salts which may be separated by crystallization, gas-liquid or liquid chromatography, selective reaction of one enantiomer with an enantiomer-specific reagent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by a separation technique, then an additional step is required to form the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

[0066] Certain compounds of Structural Formula I may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers. The present invention includes each conformational isomer of compounds of Structural Formula I and mixtures thereof.

[0067] Certain compounds of Structural Formula I may exist in zwitterionic form and the present invention includes each zwitterionic form of compounds of Structural Formula I and mixtures thereof.

[0068] The compounds of this invention can also exist as tautomers; therefore the present invention also includes all tautomeric forms.

[0069] The compounds of Formula Ia are useful in the inhibition of HIV integrase, the prevention or treatment of infection by the human immunodeficiency virus and the treatment of consequent pathological conditions such as AIDS or ARC. The treatment involves administering to a patient, in need of such treatment, a compound of Formula Ia, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate or prodrug therefor.

[0070] It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established infections or symptoms. This includes initiating treatment pre- and post-exposure to the virus. In addition, the present invention can be administered in conjunction with other anti-HIV agents, immunomodulators, antiinfectives and/or vaccines.

[0071] The compounds of the present invention are also useful in the preparation and execution of screening assays for antiviral compounds. Further, the compounds of the present invention are useful in establishing or determining the binding site of other antiviral compounds to HIV integrase, for example, by competitive inhibition.

[0072] The compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.

[0073] This invention also provides a pharmaceutical composition for use in the above-described therapeutic method. A pharmaceutical composition of the present invention comprises an effective amount of a compound of Formula I in association with a pharmaceutically acceptable carrier, excipient or diluent.

[0074] The active ingredient in such formulations comprises from 0.1 percent to 99.9 percent by weight of the formulation. By “pharmaceutically acceptable’it is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0075] The present pharmaceutical compositions are prepared by known procedures using well-known and readily available ingredients. The compositions of this invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. In making the compositions of the present invention, the active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, beadlets, lozenges, sachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, (as a solid or in a liquid medium), soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders and the like.

[0076] The compounds can be administered by a variety of routes including oral, intranasally, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal.

[0077] When administered orally, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation. For oral administration, the compound is typically formulated with excipients such as binders, fillers, lubricants, extenders, diluents, disintegration agents and the like as are known in the art.

[0078] For parenteral administration, the compound is formulated in pharmaceutically acceptable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, 5 percent dextrose, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

[0079] A compound of the present invention, or a salt or solvate thereof, can be formulated in unit dosage formulations comprising a dose between about 0.1 mg and about 1000 mg, or more, according to the particular treatment involved. An example of a unit dosage formulation comprises 5 mg of a compound of the present invention in a 10 mL sterile glass ampoule. Another example of a unit dosage formulation comprises about 10 mg of a compound of the present invention as a pharmaceutically acceptable salt in 20 mL of isotonic saline contained in a sterile ampoule.

[0080] The compounds of the present invention can also be administered to humans in a dosage range of 1 to 100 mg/kg body weight in divided doses. One preferred dosage range is 1 to 20 mg/kg body weight orally in divided doses. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the route of administration, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0081] General methods useful for the synthesis of compounds embodied in this invention are shown below. The preparations shown below are disclosed for the purpose of illustration and are not meant to be interpreted as limiting the processes to make the compounds by any other methods.

[0082] It will be appreciated by those skilled in the art that a number of methods are available for the preparation of the compounds of the present invention as provided by Structural Formula I. A compound of Structural Formula I may be prepared by processes which include processes known in the chemical art for the production of structurally analogous compounds or by a novel process described herein. A process for the preparation of a compound of Structural Formula I (or a pharmaceutically acceptable salt thereof) and novel intermediates for the manufacture of a compound of Formula I, as defined above, provide further features of the invention and are illustrated by the following procedures in which the meanings of the generic radicals are as defined above, unless otherwise specified. It will be recognized that it may be preferred or necessary to prepare a compound of Formula I in which a functional group is protected using a conventional protecting group then to remove the protecting group to provide the compound of Formula I.

[0083] Thus, there is provided a process for preparing a compound of Formula I (or a pharmaceutically acceptable salt thereof) as provided in any of the above descriptions which is selected from any of those described in the examples, including the following. As shown below in Scheme I, in one method an appropriately substituted methyl-carbonyl, such as a methyl ketone, acetylamide or acetylhydrazide, is condensed with oxalic acid ester under basic conditions to form a diketobutyric acid of the present invention. A representative procedure has been described by Gramain (Gramian, J. -F.; Remuson, R., Vallee D. J. Org. Chem. 1985, 50, 710). A variety of bases can be used to effect this reaction including LDA, LiHMDS, tBuOK, NaOMe, NaOEt, NaH or MeOCO₂MgOMe. In addition there a number of oxalic acid derivatives that have been disclosed which may be useful in the formation of the diketobutyric acid group (de las Heras, M. A.; Vaquerao, J. J.; García-Navio, J. L.; Alvarez-Builla, J. J. Org. Chem. 1996, 61, 9009). This method is generally applicable to the compounds embodied by Formula I.

[0084] Exemplification

[0085] The specific examples that follow illustrate the syntheses of the compounds of the instant invention, and are not to be construed as limiting the invention in sphere or scope. The methods may be adapted to variations in order to produce compounds embraced by this invention but not specifically disclosed. Further, variations of the methods to produce the same compounds in somewhat different manner will also be evident to one skilled in the art.

[0086] In the following experimental procedures, all temperatures are understood to be in Centigrade (C) when not specified. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (d) expressed in parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative area reported for the various shifts in the proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad singlet (bs or br s), broad doublet (bd or br d), broad triplet (bt or br t), broad quartet (bq or br q), singlet (s), multiplet (m), doublet (d), quartet (q), triplet (t), doublet of doublet (dd), doublet of triplet (dt), and doublet of quartet (dq). Examples of solvents employed for taking NMR spectra are acetone-d₆ (deuterated acetone), DMSO-d₆ (perdeuterodimethylsulfoxide), D₂O (deuterated water), CDCl₃ (deuterochloroform) and other conventional deuterated solvents such as deuterated methanol.

[0087] The abbreviations used herein are conventional abbreviations widely employed in the art. Some of which are: calcd (calculated); DMSO (dimethylsulfoxide); EtOAc (ethyl acetate); HPLC (high-pressure liquid chromatography); LC/MS (liquid chromatography, mass spectroscopy); LDA (lithium diisopropyl amide); LiHMDS (lithium bis(trimethylsilyl)amide); SiO₂ (silica gel); THF (tetrahydrofuran), Me (methyl), Et (ethyl), Ph (phenyl), tBuOK (potassium tert-butoxide), NaOMe (sodium methoxide), and NaOEt (sodium ethoxide).

[0088] Many compounds were analysed using the following LC/MS conditions:

[0089] Column: Luna 5μ C-8, 4.6×30 mm

[0090] Solvents: Solvent A: 10% CH₃CN-90% H₂O, 5 mM NH₄OAc

[0091] Solvent B: 90% CH₃CN-10% H₂O, 5 mM NH₄OAc

[0092] Gradient: 100% solvent A/0% solvent B to 0% solvent A/100% solvent B

[0093] Gradient time: 2 minutes, hold time 1 minute.

[0094] Flow rate: 4 ml/min.

[0095] Detector wavelength: 220 nm.

[0096] Spectrometry (MS) data were determined with a Micromass ZMD Platform for LC in electrospray mode.

[0097] The compounds and chemical intermediates of the present invention, described in the following examples, were prepared according to the following methods.

[0098] Method I:

[0099] Aryl halide (4.6 mmol) was dissolved in 1 mL of THF and 23 mL of 2M MeNH₂ in THF added. The resulting mixture was allowed to stir overnight resulting in a suspension. This was filtered and the solvent removed under vacuum to yield crude amine, which was taken on to the next step without further purification. This method can also be utilized with compounds similar to the aryl halide starting material.

[0100] Method II:

[0101] Step 1:

[0102] Substituted benzoic acid (50 mmol) and 1-hydroxybenzotriazolehydrate (50 mmol) were combined in a round bottom flask and dissolved in 25 mL of DMF. To this solution was added amine (50 mmol) in THF and triethylamine (150 mmol) followed by HBTU [O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate] (75 mmol). The reaction was allowed to proceed overnight after which, H₂O was added and the resulting solution extracted with ethyl acetate. The organic layer was separated, washed with H₂O, dried over Na₂SO₄, filtered and solvent removed. The crude product was isolated by flash column chromatography (SiO₂, Hexanes/ethyl acetate)

[0103] Alternatively, to a solution of amine (139 mmol), 140 mL of 1N NaOH and 130 mL of methylene chloride was added substituted benzoyl chloride (139 mmol). The resulting mixture was stirred 1 h, after which time the organic layer was separated, washed with H₂O and dried over Na₂SO₄. After filtration the solvent was removed and the product carried on to the next step without further purification. This method can also be utilized with compounds similar to the substituted benzoic acid starting material.

[0104] Step 2:

[0105] The resultant amide (123 mmol) was dissolved in 180 mL of THF. 5.51 mL of BF₃.Et₂O was added and the resulting solution heated to reflux for 15 min. The reaction was then cooled to −20-40° C. and BH₃.DMS added with a dropping funnel over 10 min. The reaction vessel was then fitted with a distillation condenser, then heated to reflux and solvent removed over 20 min. The distillation condenser was replaced with reflux condenser and the solution heated to 110° C. for 2 h. After cooling to room temp 75 mL of 6N HCl was added and then the resulting mixture heated to reflux for 1 h. The solution was then allowed to cool to room temp and 200 mL of 6 N NaOH was slowly added. The resulting mixture was extracted with Et₂O and the organic layer was washed with satd NaCl (aq.), dried over Na₂SO₄, filtered and the solvent removed under vacuum. The resulting oil was dissolved in Et₂O and 30 mL of 4N HCl (dioxane) added to form a precipitate.

[0106] Alternatively, a solution of the amide (13.2 mmol) in tetrahydrofuran (75 ml) was treated with lithium aluminum hydride (1.0 g, 26.3 mmol) and the resulting mixture was heated under reflux for 1 h. The cooled mixture was hydrolyzed by the successive addition of water (1 ml), 15% sodium hydroxide solution (1 ml) and water (3 ml). The solid formed was filtered and the filtrate was concentrated under reduce pressure. Chromatography of the residue on silica gel (elution dichloromethane/methanol) gave the pure product.

[0107] Method III:

[0108] Aryl aldehyde (2.6 mmol) and 3.9 mL of 2 M methyl amine in THF were dissolved in 0.5 mL of EtOH followed by the addition of NaBH₄ (13 mmol). The resulting mixture was stirred overnight, after which it was filtered and the filtrate acidified with 10% H₂SO₄ (aq.). This was washed with Et₂O then neutralized with 10 N NaOH. The resulting mixture was extracted with Et₂O, the organic layer separated and washed with satd NaCl, dried over Na₂SO₄, filtered and the solvent removed under vacuum to yield pure amine. This method can also be utilized with compounds similar to the aryl aldehyde starting material.

[0109] Method IV:

[0110] To a solution of amine (7.3 mmol) in a 1:1 mixture of 50 mL of CH₂Cl₂ and Satd NaHCO₃ (aq.) was added AcCl (14.7 mmol). The resulting mixture was stirred overnight after which the organic layer was separated, dried over Na₂SO₄, filtered and solvent removed to yield pure product. This method can also be utilized with amine compounds similar to the above-identified starting material.

[0111] Method V:

[0112] Step 1:

[0113] Benzyl halide (6.67 mmol) was dissolved in 5 ml of THF. To this was added 5 ml of 40% (aq.) methylamine and the resulting mixture stirred 15 min. The reaction mixture was transferred to a separatory funnel, diluted with 100 ml H₂O and extracted with 100 ml of ethyl acetate. The organic solution was washed with brine, dried over Na₂SO₄ then filtered and the solvent removed. The crude product was purified by column chromatography (SiO₂, 2-10% EtOH/CH₂Cl₂). This method can also be utilized with compounds similar to the benzyl halide starting material.

[0114] Step 2:

[0115] The intermediate amine (4.6 mmol) synthesized above was dissolved in 30 ml CH₂Cl₂. Satd. (aq.) NaHCO₃ was added followed by CH₃COCl (5.0 mmol) and the resulting mixture stirred for 1 h. The organic layer was separated, washed with brine dried over Na₂SO₄ then filtered and the solvent removed to yield pure product.

[0116] Method VI:

[0117] Step 1:

[0118] Benzyl halide (11.1 mmol) was dissolved in 11 mL of THF, to which was added R₃NH₂ (22.1 mmol). The resulting reaction was stirred for 2 h during which a white precipitate forms. The solid was filtered and washed with THF. Solvent was removed from the THF solution under vacuum. This method can also be utilized with compounds similar to the benzyl halide starting material.

[0119] Step 2:

[0120] The product of step 1 was dissolved in 75 mL of methylene chloride, to which 75 mL of satd NaCO₃ (aq.) was added followed by acetyl chloride (22.1 mmol). The mixture was stirred for 2 hours. The organic layer was separated, washed with satd NaCl, dried over Na₂SO₄, filtered and the solvent removed under vacuum to yield crude product. The product was purified by flash column chromatography (SiO₂, EtOAc/Hexanes).

[0121] Method VII:

[0122] Sodium hydride (60% in mineral oil) (27.5 mmol) was measured into a round bottom flask and triturated with hexanes. To this was added N-alkylacetamide (13.8 mmol) dissolved in 34 mL of toluene. To the resulting suspension was added benzyl halide (6.9 mmol) and the reaction mixture stirred overnight. The mixture was then filtered and the solvent removed under vacuum. The product was purified by flash column chromatography (SiO₂, EtOH/methylene chloride). This method can also be utilized with compounds similar to the N-alkylacetamide starting material.

[0123] Method VIII:

[0124] A solution of amine (7.63 mmol), as in Method IV, in a mixture of pyridine (10 ml) and acetic anhydride was stirred at 22° C. for 2 h. The excess reagents were evaporated in vacuo and the residue was filtered on a silica gel pad (elution toluene-ethyl acetate) to give pure product.

[0125] Method IX:

[0126] Acetyl amide (9.92 mmol) was dissolved in 20 ml of anhydrous THF under an N₂ atmosphere then cooled to −78° C. To this was added 30 ml of 1M LiHMDS (lithium bis(trimethylsilyl)amide) and the reaction mixture stirred for 20 min. at which point dimethyl oxalate (14.9 mmol) dissolved in 8 ml of THF was added. The reaction was allowed to continue at −78° C. for 20 min. then warmed to 0° C. and stirred an additional 45 min. 1 N HCl was added and the resulting mixture extracted with EtOAc. The organic solution was washed with brine, dried over Na₂SO₄ then filtered and the solvent removed. The crude product was purified by reverse phase preparative HPLC (C₁₈, MeOH/H₂O (0.1% TFA)-gradient), flash column chromatography (SiO₂, Hexanes/EtOAc) or carried onto the next step without further purification.

[0127] Alternatively, acetyl amide (54 mmol) and dimethyl oxalate (81 mmol) were dissolved in 54 mL of THF and cooled to 0° C. To this solution was added 108 mL of 1N LiHMDS (THF) dropwise via an addition funnel. The resulting mixture was stirred at 0° C. for 1 h, after which the reaction was quenched with 1N HCl. The solution was extracted with methylene chloride, the organic layer separated, dried over Na₂SO₄, filtered and the solvent removed under vacuum to yield crude product. The compound was purified by flash chromatography (SiO₂, Hexanes/ethyl acetate).

[0128] This method can also be utilized with compounds similar to the acetyl amide starting material.

[0129] Method X:

[0130] To a solution of methyl ester (0.33 mmol) dissolved in 0.4 ml of MeOH was added 0.4 ml of 1N NaOH. After stirring for 1 h, 0.4 ml of 1N HCL was added and the resulting mixture extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄ then filtered and the solvent removed under vacuum. The crude product was purified by reverse phase preparative HPLC (C18, MeOH/H₂O (0.1% TFA)). This method can also be utilized with compounds similar to the above-identified starting material.

[0131] Method XI:

[0132] The methyl ester (5.5 mmol) was suspended in 16.5 mL of 1N NaOH (aq.) with rapid stirring. To this was added THF, dropwise until all the solid had dissolved. After stirring the resulting solution an additional 20 min., it was transferred to a separatory funnel, washed with CH₂Cl₂, acidified with 1 N HCl and the product extracted with EtOAc. The organic layer was dried over Na₂SO₄, filtered and the solvent removed to yield crude product. The crude product could be purified by preparative HPLC (C₁₈, MeOH/H₂O, 0.1% TFA). This method can also be utilized with methyl ester compounds similar to the above-identified starting material.

[0133] Method XII:

[0134] Acetyl amide (2.0 mmol) was dissolved in 10 mL of THF and the resulting solution cooled to −78° C., after which 4.0 mL of 1N LIHMDS (in THF) was added. The resulting solution was allowed to stir for 20 min. Dimethyloxalate (0.36 grams, 3.0 mmol), dissolved in 2 mL of THF was then added and the reaction stirred for 3 h at −78° C. The reaction was warmed to 0° C. and stirred an additional 20 min. before being quenched with 1 N HCl. The mixture was extracted with EtOAc, and the organic layer dried over MgSO₄. The solution was filtered and solvent removed to yield the crude methyl ester. The crude ester was either taken on to the next step crude or purified by preparative HPLC (C₁₈, MeOH/H₂O-0.1% TFA)

[0135] The intermediate methyl ester was dissolved in a 1:1 mixture of 1N NaOH and THF and stirred for 2 h. THF was then removed under vacuum and the solution acidified with 1 N HCl. Solvent was then removed under vacuum to yield crude product, which was purified by preparative HPLC (C₁₈, MeOH/H₂O-0.1% TFA).

[0136] This method can also be utilized with compounds similar to the acetyl amide starting material.

[0137] Method XIII:

[0138] Preparation of (Z)-2,2-Dimethyl-5-(carboxymethylene)-1,3-dioxolane-4-one (IV)

[0139] Step 1: Preparation of (S)-(+)-2,2-Dimethyl-5-oxo-1,3-dioxolane-4-acetic Acid, tert-butyldiphenylsilyl Ester (I):

[0140] A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid (2.08 g, 11.9 mmol), which was derived from L-malic acid by means known in the art, in dry dichloromethane (20 ml) was treated with triethylamine (1.83 ml, 13.1 mmol) followed by a solution of t-butylchlorodiphenylsilane (3.44 g, 12.5 mmol) in dichloromethane (5 ml) added dropwise over 5 minutes. After 3 hours at 22° C., the reaction mixture was diluted with toluene (250 ml) washed with water, saturated sodium bicarbonate, brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure and chromatography of the residue on silica gel (4×12 cm) using a mixture of toluene and ethyl acetate (0-2%) as eluent gave 4.90 g (99%) of the title material as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ: 1.13 (s, 9), 1.58 (s, 3), 3.05 (m, 2), 4.79 (dd, 1, J=4, 7), 7.4-7.8 (m, 10).

[0141] Step 2: Preparation of 4-Bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic Acid, tert-butlydiphenylsilyl Ester (II):

[0142] A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tert-butyldiphenylsilyl ester (21.65 g, 52.4 mmol) in carbon tetrachloride (160 ml) was treated with N-bromosuccinimide (9.35 g, 52.4 mmol) and 2,2′-azobisisobutyronitrile (200 mg) and the resulting mixture was heated under reflux (bath temperature 85° C.) while irradiating with a 500 watt lamp. After 10 minutes, the reaction mixture was cooled and the succinimide was filtered. The solvent was evaporated under vacuum to give the title bromide as a light yellow oil (−26 g) which was used immediately for the next step. ¹H NMR (400 MHz, CDCl₃) δ: 1.12 (s, 9), 1.41 (s, 3), 1.80 (s, 3), 3.80 (m, 2), 7.3-7.7 (m, 10).

[0143] Step 3: Preparation of (Z)-2,2-Dimethyl-5-(tert-butyldiphenylsilyloxycarbonyl-methylene)-1,3-dioxolan-4-one (III):

[0144] A solution of 4-bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tert-butyldiphenylsilyl ester (-26 g, 52.4 mmol) in dry tetrahydrofuran (160 ml) was cooled to 0° C. and treated dropwise over 5 minutes with 1,8-diazabicyclo [5,4,0] undec-7-ene (12.7 g, 78.8 mmol) and the resulting mixture was stirred at 5° C. for 1.5 hour. The solid formed was filtered and washed with a small amount of tetrahydrofuran. The filtrate was used as such for the next step.

[0145] Alternatively, the reaction mixture can be diluted with toluene, washed with water, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent gave an oil which was chromatographed on silica gel using a mixture of toluene and ethyl acetate (0-2%) as eluent. The title ester was obtained as an oil in 30-50% yield. ¹NMR (400 MHz, CDCl₃) δ: 1.16 (s, 9), 1.76 (s, 6), 5.97 (s, 1), 7.4-7.8 (m, 10)

[0146] Step 4: Preparation of (Z)-2,2-dimethyl-5-(carboxymethylene)-1,3-dioxolan-4-one (IV) from Pure (III): A solution of pure (Z)-2,2 dimethyl-5-(t-butyldiphenylsilyloxycarbonylmethylene) -1,3-dioxolan-4-one (2.80 g, 6.82 mmol) in tetrahydrofuran (40 ml) was treated at 22° C. with acetic acid (2 ml) followed by 6.8 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 15 minutes at 22° C., the reaction mixture was diluted with ethyl acetate, washed with water, brine and dried (magnesium sulfate). The solvent was concentrated under reduced pressure and the residue was triturated with toluene to give 1.00 g (85%) of the title compound as a white crystalline material: mp 203-204° C. (dec.). IR (KBr) v max (cm ⁻¹): 1805, 1707 and 1662. ¹H NMR (400 MHz, CDCl₃) δ: 1.78 (s, 6), 5.89 (s, 1). Anal. calcd for C₇H₈O₅: C, 48.84; H, 4.68; found: C, 48.84; H, 4.65.

[0147] Preparation of (Z)-2,2-dimethyl-5-(carboxymethylene)-1,3-dioxolan-4-one (IV) from crude (III):

[0148] A solution of the crude (Z)-2,2-dimethyl-5-(tert-butyldiphenylsilyloxycarbonyl methylene)-1,3-dioxolan-4-one (52.4 mmol) in tetrahydrofuran (200 ml) was treated with acetic acid (13 ml) followed with 50 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 15 minutes at 22° C., the reaction mixture was filtered and the filtrate was concentrated in vacuo. Trituration of the residue with toluene gave 6.3 g (70% for three steps) of the title material as a white solid (>95% pure by ¹HNMR)

[0149] Method XIV:

[0150] A solution of (Z)-2,2-dimethyl -5-(carboxymethylene)-1,3-dioxolan-4-one (0.214 g, 1.24 mmol) and amine (1.24 mmol) in acetonitrile (15 ml) was treated at 22° C. with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (0.550 g, 1.24 mmol) followed by triethylamine (0.18 ml, 1.29 mmol). After 2 hours, the reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate) gave amide as an oil or solid. This method can also be utilized with amine compounds similar to the above-identified starting material.

[0151] Method XV:

[0152] The amine (0.1 mmol) was treated with 0.5 ml of a 0.3M stock solution of benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP®) (1.5 eq) and triethylamine (1.5 equivalent) in dichloromethane followed by 0.5 ml of a 0.2 M solution of (Z)-2,2-dimethyl-5-(carboxymethylene)-1,3-dioxolan-4-one (1 eq) in a mixture of dichloromethane —N,N-dimethylformamide (10: 1). After 16 h at 22° C., the mixtures were purified using a Shimadzu automated preparative HPLC system (Primesphere C-8, 5μ, 21×100 mm, H₂O 5 mM NH₄OAc-acetonitrile). This method can also be utilized with compounds similar to the amine starting material.

[0153] Method XVI:

[0154] Preparation of (Z)-2,2-Dimethyl-5-(carboxymethylene)-1,3-dioxolane-4-one (IV)

[0155] Step 1: Preparation of (+)-2,2-Dimethyl-5-oxo-1,3-dioxolane-4-acetic Acid, tert-butyldimethylsilyl Ester (V):

[0156] A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid (13.20 g, 75.8 mmol), which was derived from L-malic acid by means known in the art, in N,N-dimethylformamide (25 ml) was treated at 22° C. with imidazole (10.56 g, 0.155 mmol) followed by tert-butyldimethylsilyl chloride (12.0 g, 79.6 mmol) and the resulting mixture was stirred at 22° C. for 18 h. The reaction mixture was then diluted with toluene (500 ml), washed with water (×3), saturated sodium bicarbonate and brine. After drying (magnesium sulfate), the solvent was evaporated under reduced pressure to give an oil. Distillation under vacuum gave 20.9 g (96%) of the title material as a clear oil : Bp 80-90° C./0.1 torr (bulb to bulb distillation, air bath temperature). ¹H NMR (400 MHz, CDCl₃) δ: 0.33 (s, 3), 0.36 (s, 3), 1.00 (s, 9), 1.11 (s, 3), 1.37 (s, 3), 2.72 (m, 2), 4.35 (dd, 1, J=4, 6).

[0157] Step 2: Preparation of 4-Bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tertbutyldimethylsilyl ester (VI):

[0158] A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, t-butyldimethylsilyl ester (20.9 g, 72.4 mmol) in carbon tetrachloride (200 ml) was treated with N-bromosuccinimide (14.18 g, 79.6 mmol) and 2,2′-azobisisobutyronitrile (0.30 g) and the resulting mixture was heated under reflux while irradiating with a 500 W lamp. After ˜5 min., a mild exothermic reaction was observed and the mixture was heated for an additional 5 min. The reaction mixture was then cooled in an ice bath and the floating succinimide was filtered and washed with a small amount of carbon tetrachloride. The filtrate was used immediately as such for the next step. ¹H NMR (400 MHz, CDCl₃) δ: 0.27 (s, 3), 0.28 (s, 3), 0.94 (s, 9), 1.66 (s, 3), 1.84 (s, 3), 3.62 (m, 2).

[0159] Step 3: Preparation of (Z)-2,2-Dimethyl-5-(tert-butyldimethylsilyloxycarbonyl-methylene)-1,3-dioxolane-4-one (VII):

[0160] The solution of crude 4-bromo-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid, tert-butyldimethylsilyl ester (72.4 mmol) in carbon tetrachloride (-220 ml) was cooled to 0-5° C. and treated dropwise over 10 min. and under good stirring with a solution of 1,8-diazabcyclo 5,4,0 undec-7-ene (12.1 g, 79.6 mmol) in dry tetrahydrofuran (125 ml). A heavy precipitate was formed which gradually became a granular solid. After 1 h, the solid obtained was filtered and washed with a small amount of tetrahydrofuran. The filtrate was concentrated under reduced pressure to give a light orange oil which was used as such for the next step.

[0161] Step 4: Preparation of (Z)-2,2-Dimethyl-5-(carboxymethylene)-1,3-dioxolan-4-one (V):

[0162] The crude (Z)-2,2-dimethyl-5-(tert-butyldimethylsilyloxycarbonylmethylene)-1,3-dioxolan-4-one (72.4 mmol) in tetrahydrofuran (50 ml) was treated at 22° C. with acetic acid (13 ml, 0.227 mmol) followed by 73 ml (73.0 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. After 1 h at 22° C., the reaction mixture was diluted with ethyl acetate (500 ml), washed with water, brine and dried (anhydrous magnesium sulfate). Evaporation of the solvent under reduced pressure and trituration of the residual solid with toluene (50 ml) gave 7.70 g (62% for 3 steps) of the title Z-isomer as a white crystalline solid. Concentration of the mother liquors yielded another 0.2 g of a 75:25 mixture of Z and E isomers. Z-Isomer; ¹H NMR (400 MHz, CDCl₃) δ: 1.78 (s, 3), 5.89 (s, 1). E-Isomer: ¹H NMR (400 MHz, CDCl₃) δ: 1.80 (s, 3), 6.03 (s, 1).

[0163] Preparation of (Z)-2,2-Dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolan-4-one (VIII):

[0164] A mixture of (Z)-2,2-dimethyl-5-(carboxymethylene)-1,3-dioxolan-4-one (0.50 g, 2.9 mmol) in dry dichloromethane (10 ml) was treated at 22° C. with oxalyl chloride (0.5 ml, 5.8 mmol) followed by a trace (capillary) of N,N-dimethylformamide. After 1 h at 22° C., the clear solution was concentrated in vacuo to give 0.55 g (quantitative) of the title acid chloride as a white crystalline solid.

[0165] Method XVII:

[0166] (Z)-2,2-Dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolane (1.3 mmol) was dissolved in 5 mL of THF. To this was added an amine (1.5 mmol) followed by Et₃N (2.6 mmol). The resulting slurry was stirred for 2 h then filtered. The mother liquor was isolate, and the solvent removed under vacuum to yield crude product which was purified by flash column chromatography (SiO₂, CH₂Cl₂/EtOH). This method can also be utilized with amine compounds similar to the above-identified starting material.

[0167] Method XVIII:

[0168] A solution of dioxolane (0.62 mmol) in tetrahydrofuran (5 ml) was treated with 1 ml of 1 M aqueous sodium hydroxide and the resulting clear solution was stirred at 22° C. for 30 minutes. The reaction mixture was then acidified with 2 N hydrochloric acid and diluted with ethyl acetate. The organic phase was washed with brine, dried (magnesium sulfate) and evaporated under reduced pressure. This method can also be utilized with dioxolane compounds similar to the above-identified starting material.

[0169] Method XIX:

[0170] Dioxolane(˜0.05 mmol) in a mixture of tetrahydrofuran (0.5 ml) and water (0.3 ml) was treated at 22° C. with 0.15 ml of 1 M aqueous sodium hydroxide and the resulting mixture was stirred for 1.5 h. The reaction mixture was then quenched by the addition of 0.3 ml of 1M trifluoroacetic acid in acetonitrile and filtered on a Varian Bond Elute C-18 cartridge (1.5 g) using water and then water-acetonitrile (1:1) as eluent.

[0171] If not commercially available, a necessary starting material for the preparation of a compound of Formula I may be prepared by a procedure which is selected from standard techniques of organic chemistry including aromatic and heteroaromatic substitution and transformation, from techniques which are analogous to the syntheses of known, structurally similar compounds, and techniques which are analogous to the above described procedures or procedures described in the Examples. It will be clear to one skilled in the art that a variety of sequences is available for the preparation of the starting materials. Starting materials which are novel provide another aspect of the invention. This method can also be utilized with dioxolane compounds similar to the above-identified starting material.

[0172] Method XX:

[0173] To a solution of dioxobutyric acid (0.58 mmol), 1-hydroxybenzotriazole hydrate (BtOH.H₂O) (0.58 mmol), amine (0.75 mmol) and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (0.88 mmol) in 4 mL of DMF was added Et₃N (1.72 mmol). The resulting mixture was stirred overnight, then diluted with EtOAc, washed H₂O and dried over MgSO₄. After filtration the solvent was removed under vacuum to yield crude product which was purified by preparative HPLC (C₁₈, MeOH/H₂O-0.1% TFA). This method can also be utilized with compounds similar to the dioxobutyric acid starting material.

EXAMPLE 1 Intermediate 1A: Methyl 4-(4-fluorobenzyloxy)-benzoate

[0174]

[0175] A mixture of methyl p-hydroxybenzoate (4.38 g, 28.8 mmol), p-fluorobenzyl chloride (5.0 g, 34.6 mmol) and anhydrous potassium carbonate (10 g) in acetone (250 ml) was heated under reflux for 24 h. The solid was then filtered and the filtrate was evaporated under reduced pressure. Crystallization of the residue from hexane gave 7.20 g (96%) of the title ester as white plates: mp 93-94° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.9 (3H, s, OCH₃), 5.1 (2H, s, CH₂), 7.0 (2H, d, J=8.8 Hz, aromatics), 7.11 (2H, m, aromatics), 7.43 (2H, m, aromatics), 8.02 (2H, d, J=8.8 Hz, aromatics). Anal. Calcd for C₁₅H₁₃FO₃: C, 69.22; H, 5.03. Found: C 68.89, H 4.69.

[0176] Intermediate 1B: 4-(4-Fluorobenzyloxy)-benzoic Acid

[0177] A mixture of Intermediate 1A (7.2 g, 27.6 mmol) in 80% aqueous ethanol (100 ml) was treated with sodium hydroxide (3.5 g) and the resulting mixture was heated at 50° C. for 2 h. The solvent was evaporated under reduced pressure and the residual solid was diluted with water and acidified with concentrated hydrochloric acid (20 ml). Filtration of the resulting solid and crystallization from ethyl acetate gave 6.05 g (89%) of the title acid as white plates: mp 213-215° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 5.16 (2H, s, CH₂), 7.1 (2H, d, J=8.9 Hz, aromatics), 7.24 (2H, m, aromatics), 7.53 (2H, m, aromatics), 7.9 (2H, d, J=0.9 Hz, aromatics) and 12.7 (1H, s, OH). Anal. Calcd for C₁₄H₁₁FO₃: C 68.29, H 4.50. Found: C 68.30, H 4.41.

[0178] Intermediate 1C: 4-(4-Fluorobenzyloxy)-N-methyl-benzylamine

[0179] Intermediate 1C was prepared from Intermediate 1B using Method II, step 2. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.47 (3H, s, NCH₃), 3.72 (2H, s, NCH₂), 5.03 (2H, s, OCH₂), 6.95 (2H, d, J=8.6 Hz, aromatics), 7.09 (2H, m, aromatics), 7.27 (2H, d, J=8.6 Hz, aromatics) 7.42 (2H, m, aromatics). HRMS (ESI+) calculated for C₁₅H₁₇FNO [M+H]: 246.1294: found: 246.1285.

[0180] Intermediate 1D: N-{4-(4-Fluorobenzyloxy)-benzyl}-N-methylacetamide

[0181] Intermediate 1D was prepared from Intermediate 1C using Method VIII. Solid: mp 82-83° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.16 and 2.19 (3H, 2 s, COCH₃), 2.93 and 2.94 (3H, 2 s, NCH₃), 4.48 and 4.54 (2H, 2 s, NCH₂), 5.03 and 5.04 (2H, 2 s, OCH₂), 6.95-7.44 (8H, m, aromatics). Anal. Calcd for C₁₇H₁₈FNO₂: C 71.06, H 6.31, N 4.87. Found: C 70.99, H 6.23, N 4.74.

[0182] Intermediate 1E: 3-{[4-(4-Fluoro-benzyloxy)-benzyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid Methyl Ester

[0183] Intermediate 1E was prepared from Intermediate 1D using Method IX. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 3.01 (3H, s, NCH₃), 3.89 and 3.92 (3H, 2 s, OCH₃), 4.54 and 4.60 (2H, 2 s, NCH₂), 5.03 (2H, s, OCH₂), 6.31 and 6.38 (1H, 2 s, CH), 6.94-7.44 (8H, m, aromatics). HRMS (MAB N₂) calculated for C₂₀H₂₀FNO₅ [M⁺]: 373.1314: found: 373.1320.

[0184] Compound 1: 3-{[4-(4-Fluoro-benzyloxy)-benzyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0185] Compound 1 was prepared from Intermediate 1E using Method XI. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.93 and 2.94 (3H, 2 s, NCH₃), 4.45 and 4.52 (2H, 2 s, NCH₂), 4.94 (2H, s, OCH₂), 6.27 and 6.35 (1H, 2 s, CH), 6.85-7.35 (8H, m, aromatics). HRMS (MAB N₂ ) calculated for C₁₉H₁₈FNO₅ [M⁺]: 359.1157: found: 359.1167, δ0.5 ppm.

EXAMPLE 2

[0186] Intermediate 2A: 3-{1-Hydroxy-1-(4-fluorophenyl)-methyl}-N-methyl-benzamide

[0187] A solution of 3-bromo-N-methylbenzamide (3.48 g, 16.25 mmol) in dry tetrahydrofuran (100 ml) was cooled to −78° C. and treated dropwise over 10 min. with 13 ml (32.5 mmol) of a 2.5 M solution of n-butyllithium in hexane. After 15 min. at −78° C., a solution of 4-fluorobenzaldehyde (2.5 g, 20.1 mmol) in tetrahydrofuran (10 ml) was added dropwise over 10 min. and the resulting mixture was stirred for another 45 min at the same temperature. The temperature was then allowed to reach −20° C. and the mixture was quenched by the addition of saturated ammonium chloride. The reaction mixture was then extracted with ethyl acetate and the organic layer was washed with 0.1N hydrochloric acid, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and crystallization of the residue from ethyl acetate gave 1.60 g (38%) of the title compound as a white solid: mp: 138-139° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.0 and 3.01 (3H, 2 s, NCH₃), 5.88 (1H, s, CH), 6.19 (1H, broad, NH), 7.03 (2H, m, aromatics), 7.36 (2H, m, aromatics), 7.41 (1H, t, J=7.6 Hz, aromatic), 7.49 (1H, d, J=7.6 Hz, aromatic), 7.66 (1H, d, J=7.6 Hz, aromatic), 7.79 (1H, s, aromatic). Anal. Calcd for C₁₅H₁₄FNO₂: C, 69.49; H, 5.44; N 5.40. Found: C 69.41, H 5.41, N5.63.

[0188] Intermediate 2B: 3-(4-Fluorobenzyl)-N-methyl-benzamide

[0189] A solution of Intermediate 2A (1.0 g, 3.85 mmol) in ethyl acetate (150 ml) and acetic acid (1 ml) was hydrogenated over 0.5 g of 10% palladium on activated carbon and under 45 psi of hydrogen for 24 h. After filtration the solvent was evaporated under reduce pressure. Crystallization of the residue from a mixture of ethyl acetate and hexane gave 0.778 g of the title amide as white needles: mp 93-94° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.02 and 3.03 (3H, 2 s, NCH₃), 4.01 (2H, s, CH₂), 6.12 (1H, broad, NH), 7.0 (2H, m, aromatics), 7.14 (2H, m, aromatics), 7.32 (1H, d, J=7.6 Hz, aromatic), 7.37 (1H, t, J=7.6 Hz, aromatic), 7.59 (1H, d, J=7.6 Hz, aromatic), 7.62 (1H, s, aromatic). Anal. Calcd for C₁₅H₁₄FNO: C, 74.06; H, 5.80; N 5.76. Found: C 73.74, H 5.87, N 5.74.

[0190] Intermediate 2C: 3-(4-Fluorobenzyl)-N-methyl-benzylamine

[0191] Intermediate 2C was prepared from Intermediate 2B using Method II, step 2. ¹HNMR 400 MHz (C₆D₆) 6 (ppm) δ 2.3 (3H, s, NCH₃), 3.59 (2H, s, CH₂), 3.76 (2H, s, CH₂), 6.85-7.25 (8H, m, aromatics). MS (ESI⁺) (m/z) δ 230 (M+H).

[0192] Intermediate 2D: N-{3-(4-Fluorobenzyl)-benzyl}-N-methylacetamide

[0193] Intermediate 2D was prepared from Intermediate 2C using Method VIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.16 and 2.17 (3H, 2 s, COCH₃), 2.92 and 2.94 (3H, 2 s, NCH₃), 3.95 and 3.97 (2H, 2 s, CH₂), 4.51 and 4.57 (2H, s, NCH₂), 6.96-7.31 (8H, m, aromatics). MS (ESI⁺) (m/z): 272 (M+H). Anal. Calcd for C₁₇H₁₈FNO: C 75.25, H 6.69, N5.16. Found: C 74.99, H 6.75, N 5.08.

[0194] Intermediate 2E: 3-{[3-(4-Fluoro-benzyl)-benzyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid Methyl Ester

[0195] Intermediate 2E was prepared from Intermediate 2D using Method IX. ¹HNMR 400 MHz (CDCl₃) δ (ppm) mixture of rotamers; 3.01 and 3.02 (3H, 2 s, NCH₃), 3.88, 3.92 and 3.96 (5H, 3 s, CH₂ and OCH₃), 4.58 and 4.64 (2H, 2 s, NCH₂), 6.32 (1H, s, CH), 6.97-7.54 (8H, m, aromatics). HRMS (MAB N₂) calculated for C₂₀H₂₀FNO₄ [M⁺]: 357.1376: found: 357.1375.

[0196] Compound 2: 3-{[3-(4-Fluoro-benzyl)-benzyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0197] Compound 2 was prepared from Intermediate 2E using Method XI. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 3.02 and 3.04 (3H, 2 s, NCH₃), 3.76 (2H, s, CH₂), 4.56 and 4.64 (2H, 2 s, NCH₂), 6.37 (1H, s, CH), 6.96-7.33 (8H, m, aromatics). HRMS (MAB N₂) calculated for C₁₉H₁₈FNO₄ [M⁺] 343.12198: found: 343.12234, δ-1.0 ppm.

EXAMPLE 3

[0198] Intermediate 3A: Methyl 3-(4-fluorobenzyloxy)-benzoate

[0199] Reaction of methyl 3-hydroxybenzoate with p-fluorobenzyl chloride as described in the preparation of Intermediate 1A gave the title ester as white prisms: mp 58-59° C. (hexane). ¹HNMR 400 MHz —(CDCl₃) δ (ppm): 3.94 (3H, s, OCH₃), 5.1 (2H, s, OCH₂), 7.09-7.69 (8H, m, aromatics). Anal. Calcd for C₁₅H₁₃FO₃: C 69.22, H 5.03. Found: C 69.08, H 4.97.

[0200] Intermediate 3B: 3-(4-Fluorobenzyloxy)-benzoic Acid

[0201] Saponification of methyl 3-(4-fluorobenzyloxy)-benzoate as described in the preparation of Intermediate 1B gave the title acid as white needles: mp 145-146° C. (ethyl acetate). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 5.11 (2H, s, OCH₂), 7.12 (2H, m, aromatics), 7.24 (1H, m, aromatics), 7.45 (3H, m, aromatics), 7.75 (2H, m, aromatics). Anal. Calcd for C₁₄H₁₁FO₃: C 68.29, H 4.50. Found: C 68.39, H 4.43.

[0202] Intermediate 3C: 3-(4-Fluorobenzyloxy)-N-methyl-benzylamine

[0203] Intermediate 3C was prepare from Intermediate 3B using Method II, step 2. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.48 (3H, s, NCH₃), 3.72 (2H, s, NCH₂), 5.05 (2H, s, OCH₂), 6.9-7.45 (8H, m, aromatics). MS (ESI⁺) (m/z): 246 (M+H).

[0204] Intermediate 3D: N-{3-(4-Fluorobenzyloxy)-benzyl}-N-methylacetamide

[0205] Intermediate 3D was prepared from Intermediate 3C using Method VIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.15 and 2.16 (3H, 2 s, COCH₃), 2.91 and 2.94 (3H, 2 s, NCH₃), 4.49 and 4.55 (2H, 2 s, NCH₂), 5.01 (2H, s, OCH₂), 6.75;7.42 (8H, m, aromatics). MS (ESI⁺) (m/z): 288 (M+H).

[0206] Intermediate 3E: 3-{[3-(4-Fluoro-benzyloxy)-benzyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid Methyl Ester

[0207] Intermediate 3E was prepared from Intermediate 3D using Method IX. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.99 and 3.01 (3H, 2 s, NCH₃), 3.86 and 3.9 (3H, 2 s, OCH₃), 4.55 and 4.62 (2H, 2 s, NCH₂), 5.01 (2H, s, OCH₂), 6.29 (1H, s, CH), 6.7-7.41 (8H, m, aromatics). HRMS (MAB N₂) calculated for C₂₀H₂₀FNO₅ [M⁺]: 373.1325: found: 373.1326.

[0208] Compound 3: 3-{[3-(4-Fluoro-benzyloxy)-benzyl]-methyl-carbamoyl}-2-hydroxy-acrylic acid

[0209] Compound 3 was prepared from Intermediate 3E using Method XI. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 3.02 and 3.05 (3H, 2 s, NCH₃), 4.58 and 4.65 (2H, 2 s, NCH₂), 5.03 (2H, s, OCH₂), 6.38 (1H, s, CH), 6.79-7.43 (8H, m, aromatics). HRMS (MAB N₂) calculated for C₁₉H₁₈FNO₅ [M⁺]: 359.1169: found 359.1170, δ-0.2 ppm.

EXAMPLE 4

[0210] Intermediate 4A: [Bis-(4-chloro-phenyl)-methyl]-methyl-amine

[0211] A solution of 4,4′-dichlorobenzhydryl chloride (3.22 g, 11.85 mmol) in a 1.85 M solution of methylamine in tetrahydrofuran (40 ml) was heated at 125° C. in a pressure vessel for 24 h. The cooled reaction mixture was diluted with ethyl acetate, washed with sodium carbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate 8:2) gave 2.12 g (67%) of the title amine as a clear oil. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.57 (3H, s, NCH₃), 4.85 (1H, s, CH benzhydryl), 7.0-7.53 (8H, m, aromatics). MS (ESI⁺) (m/z): 266 (M+H).

[0212] Intermediate 4B: N-[Bis-(4-chloro-phenyl)-methyl]-N-methyl-acetamide

[0213] Intermediate 4B was prepared from Intermediate 4A using Method VIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.17 (3H, s, COCH₃), 2.66 and 2.75 (3H, 2 s, NCH₃), 6.13 (1H, s, CH benzhydryl), 7.06 and 7.3 (2×4H, m, aromatics).

[0214] Intermediate 4C: 3-{[Bis-(4-chloro-phenyl)-methyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid Methyl Ester

[0215] Intermediate 4C was prepared from Intermediate 4B using Method IX. ¹HNMR 400 MHz (CDCl₃) δ (ppm) mixture of rotamers; 2.79 and 2.89 (3H, 2 s, NCH₃), 3.88 and 3.92 (3H, 2 s, OCH₃), 6.31, 6.33 and 6.35 (2H, 3 s, CH benzhydryl and CH), 7.28 (4H, m, aromatics), 7.37 (4H, m, aromatics). HRMS (ESI+) calculated for C₁₉H₁₉Cl₂NO₄ [M+H⁺]: 394.0613: found: 394.0609.

[0216] Compound 4: 3-{[Bis-(4-chloro-phenyl)-methyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0217] Compound 4 was prepared from Intermediate 4C using Method XI. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.80 and 2.89 (3H, 2 s, NCH₃), 6.31, 6.37 and 6.41 (2H, 3 s, CH benzhydryl and CH), 7.06-7.17 and 7.32-7.43 (8H, m, aromatics). HRMS (MAB N₂) calculated for C₁₈H₁₅Cl₂NO₄ [M⁺]: 379.0378: found 379.0374, δ1.1 ppm.

EXAMPLE 5

[0218] Intermediate 5A: [Bis-(4-fluoro-phenyl)-methyl]-methyl-amine

[0219] A mixture of 4,4′-difluorobenzophenone (2.18 g, 10.0 mmol) in anhydrous ethanol (15 ml) was treated successively with titanium (IV) isopropoxide (5.9 ml, 20.0 mmol), methylamine hydrochloride (1.35 g, 20.0 mmol) and triethylamine (2.8 ml, 20.0 mmol).The resulting mixture was stirred at 22° C. for 18 h and then treated with sodium borohydride (0.57 g, 15.0 mmol). After 6 h at 22° C., the reaction mixture was quenched by the addition of 2N aqueous ammonia (30 ml) and the resulting precipitate was filtered and washed with dichloromethane. The organic layer was collected and extracted with 1N hydrochloric acid. The aqueous phase was then treated with 2N aqueous sodium hydroxide (pH 11) and extracted twice with dichloromethane. The combined extracts were dried (magnesium sulfate) and concentrated. Distillation of the residue in vacuo gave 2.12 g (91%) of the title amine as a clear oil: bp 85-90° C./0.2 torr, (bulb to bulb distillation, air bath temperature). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.40 (3H, s, NCH₃), 4.68 (1H, s, CH benzhydryl), 7.0 (4H, m, aromatics), 7.35 (4H, m, aromatics). Anal. Calcd for C₁₄H₁₃F₂N: C, 72.09; H, 5.62; N 6.0. Found: C 71.76, H 5.76, N 5.84

[0220] Intermediate 5B: N-[Bis-(4-fluoro-phenyl)-methyl]-N-methyl-acetamide

[0221] Intermediate 5B was prepared from Intermediate 5A using Method VIII. Solid: mp 99-100° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.20 and 2.21 (3H, 2 s, COCH₃), 2.70 and 2.78 (3H, 2 s, NCH₃), 6.18 (1H, s, CH benzhydryl), 7.0-7.25 (8H, m, aromatics). Anal. Calcd for C₁₆H15F₂NO: C 69.81, H 5.49, N 5.09 Found: C 69.52, H 5.47, N 5.01.

[0222] Intermediate 5C: 3-{[Bis-(4-fluoro-phenyl)-methyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid Methyl Ester

[0223] Intermediate 5C was prepared from Intermediate 5B using Method IX. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.79 and 2.89 (3H, 2 s, NCH₃), 3.88 and 3.92 (3H, 2 s, OCH₃), 6.33 and 6.35 (2H, 2 s, CH benzhydryl and CH), 7-7.2 (8H, m, aromatics). MS (ESI⁺) (m/z): 362 (M+H).

[0224] Compound 5: 3-{[Bis-(4-fluoro-phenyl)-methyl]-methyl-carbamoyl}-2-hydroxy-acrylic acid

[0225] Compound 5 was prepared from Intermediate 5C using Method XI. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.82 and 2.91 (3H, 2 s, NCH₃), 6.36 and 6.41 (1H, 2 s, CH), 6.43 (1H, s, CH benzhydryl),7.1-7.4 (8H, m, aromatics). HRMS (MAB N₂) calculated for C₁₈H₁₅F₂NO₄ [M⁺]: 347.0969: found 349.0960, 6 2.6 ppm.

EXAMPLE 6

[0226] Intermediate 6A: N-[Bis-(4-methoxy-phenyl)-methyl]-N-methyl-acetamide

[0227] Intermediate 6A was prepared from bis-(4-methoxy-phenyl)-methyl]-methyl-amine (Cymerman-Craig, et al. Aust. J. Chem. 1955, 8, 385) using Method VIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.19 and 2.21 (3H, 2 s, COCH₃), 2.70 and 2.78 (3H, 2 s, NCH₃), 3.81 and 3.82 (3H, 2 s, OCH₃), 6.13 (1H, s, CH benzhydryl), 6.87 and 7.08 (2×4H, m, aromatics). Anal. Calcd for C₁₈H₂₁NO₃: C 72.22, H 7.07, N 4.68 Found: C 71.99, H 6.88, N 4.65.

[0228] Intermediate 6B: 3-{[Bis-(4-methoxy-phenyl)-methyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid Methyl Ester:

[0229] Intermediate 6B was prepared from Intermediate 6A using Method IX. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.79 and 2.89 (3H, 2 s, NCH₃), 3.84, 3.85, 3.87 and 3.92 (9H, 4 s, OCH₃), 6.30, 6.34 and 6.37 (2H, 3 s, CH benzhydryl and CH), 6.9-6.93 (4H, m, aromatics), 7.08-7.14 (4H, m, aromatics). HRMS (ESI+) calculated for C₂₁H₂₄NO₆ [M+H⁺]: 386.16037 found: 386.15890.

[0230] Compound 6: 3-{[Bis-(4-methoxy-phenyl)-methyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid:

[0231] Compound 6 was prepared from Intermediate 6B using Method XI. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.75 and 2.83 (3H, 2 s, NCH₃), 3.77, and 3.78 (6H, 2 s, OCH₃), 6.23, 6.33 and 6.36 (2H, 3 s, CH benzhydryl and CH), 6.83-6.86 (4H, m, aromatics), 6.88-7.06 (4H, m, aromatics). HRMS ESI—) calculated for C₂₀H₂₀NO₆ [M−H]⁻: 370.12906 found: 370.13003, δ-2.6 ppm.

EXAMPLE 7

[0232] Intermediate 7A: 3-(Benzhydryl-methyl-carbamoyl)-2-hydroxy-acrylic Acid Methyl Ester

[0233] Intermediate 7A was prepared from N-Bis-(phenyl)-methyl]-N-methyl-acetamide from using Method IX. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.67 and 2.83 (3H, 2 s, NCH₃), 3.79 and 3.83 (3H, 2 s, OCH₃), 6.28 (1H, s, CH benzhydryl), 6.3 and 6.31 (1H, 2 s, CH), 7-7.4 (10H, m, aromatics).

[0234] Compound 7: 3-(Benzhydryl-methyl-carbamoyl)-2-hydroxy-acrylic Acid:

[0235] Compound 7 was prepared from Intermediate 7A using Method XI. ¹HNMR 400 MHz (CDCl₃) δ (ppm) mixture of rotamers; 2.82 and 2.91 (3H, 2 s, NCH₃), 6.41 (1H, s, CH benzhydryl), 6.37 and 6.43 (1H, 2 s, CH), 7.1-7.4 (10H, m, aromatics). HRMS (MAB N₂) calculated for C₁₈H₁₇NO₄ [M⁺]: 311.1157: found 311.1154, δ1 ppm.

EXAMPLE 8

[0236] Intermediate 8A: 2,2-Bis-(4-fluoro-phenyl)-N-methyl-acetamide

[0237] A mixture of bis-(4-fluorophenyl)-acetic acid (8.07 g, 32.5 mmol) (prepared using the procedure of Takahashi,Y.et al., Chem. Lett., 1985, 1733.), in dichloromethane (30 ml) was treated at 22° C. with oxalyl chloride (5.5 ml, 65.0 mmol) and a drop of N,N-dimethylformamide. After 18 h at 22° C., the solvent and excess reagent were evaporated under reduce pressure. The residual oil was then dissolved in dry tetrahydrofuran (10 ml) and added dropwise and under good stirring to a cold (0-5° C.) mixture of methylamine hydrochloride (10.9 g, 0.16 mol), sodium hydroxide (6 g) in water (50 ml) and tetrahydrofuran (100 ml). After 1 h at 22° C., the reaction mixture was diluted with ethyl acetate, washed successively with water, 1N hydrochloric acid, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and crystallization of the residue in ethyl acetate gave 7.75 g (91%) of the title material as white needles: mp 179-180° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.86 (3H d, J=5.1 Hz, NCH₃), 4.87 (1H, s, CH) 5.65 (1H, broad, NH), 7.04 and 7.23 (2×4H, 2 m, aromatics). Anal. Calcd for C₁₅H₁₃F₂NO: C 68.96, H 5.02, N 5.36. Found: C 68.88, H 4.49, N 5.75

[0238] Intermediate 8B: [2,2-Bis-(4-fluoro-phenyl)-ethyl]-methyl-amine

[0239] A mixture of Intermediate 8A (8.68 g, 33.2 mmol) in tetrahydrofuran (50 ml) was treated with boron trifluoride diethyl etherate (4.2 ml, 33.2 mmol) and heated under reflux for 15 min. The resulting homogeneous solution was cooled at 22° C. and treated with borane-methyl sulfide complex (4.5 ml, 4.5 mmol) added dropwise over 5 min. The solution was then heated under reflux for 30 min. The tetrahydrofuran was then distilled and the residue was maintained at 110° C. for another hour. The cooled mixture was then treated dropwise with 6N hydrochloric acid (15 ml) and heated under reflux for 1 h. The mixture was cooled to 0-5° C. and 6N sodium hydroxide solution (30 ml) was added. The aqueous mixture was extracted with ether (4×), the combined extracts were dried (anhydrous sodium carbonate) and concentrated under reduce pressure. Distillation of the residue in vacuo gave 7.66 g (93%) of the title amine as a clear oil: bp 90-105° C./0.2 torr (bulb to bulb distillation, air bath temperature). ¹HNMR 400 MHz (C₆D₆) 8 (ppm): 2.27 (3H, s, NCH₃), 2.93 (2H, d, J=7.6 Hz, CH₂), 3.96 (1H, t, J=7.6 Hz, CH) and 6.91 (8H, m, aromatics). MS (ESI⁺) (m/z): 248 (M+H) Anal. Calcd for C₁₅H₁₅F₂N-0.25H₂O: C, 71.55; H, 6.21; N 5.56. Found: C 71.67, H 5.86, N 5.59.

[0240] Intermediate 8C: N-[2,2-Bis-(4-fluoro-phenyl)-ethyl]-N-methyl-acetamide

[0241] Intermediate 8C was prepared from Intermediate 8B using Method VIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 1.72 and 2.01 (3H, 2 s, COCH₃), 2.71 and 2.87 (3H, 2 s, NCH₃), 3.88 and 3.95 (2H, 2d, J=7.6 Hz and J=8.0 Hz, CH₂), 4.31 and 4.40 (1H, 2t, J=7.6 Hz and J=8.0 Hz, CH), 6.98;7.25 (8H, m, aromatics). MS (ESI⁺) (m/z): 290 (M+H).

[0242] Intermediate 8D: 3-{[2,2-Bis-(4-fluoro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid Methyl Ester

[0243] Intermediate 8D was prepared from Intermediate 8C using Method IX. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.78 and 2.84 (3H, 2 s, NCH₃), 3.88 and 3.90 (3H, 2 s, OCH₃), 3.96 and 4.03 (2H, 2d, J=8 Hz, CH₂), 4.23 and 4.42 (1H, 2t, J=8.0 Hz, CH), 5.95 and 6.14 (1H, 2 s, CH), 7.0-7.24 (8H, m, aromatics). MS (ESI⁺) (m/z): 376 (M+H).

[0244] Compound 8: 3-{[2,2-Bis-(4-fluoro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0245] Compound 8 was prepared from Intermediate 8D using Method XI. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.77 and 2.84 (3H, 2 s, NCH₃), 3.94 and 4.02 (2H, 2 d, J=8.1 Hz and J=8.2 Hz, CH₂), 4.21 and 4.40 (1H, 2t, J=8.1 Hz and J=8.2 Hz, CH), 6.0 and 6.18 (1H, 2 s, CH), 6.98-7.25 (8H, m, aromatics) HRMS (ESI⁻) calculated for C₁₉H₁₆F₂NO₄ [M−H]⁻: 360.1036: found: 360.1049, 6-0.5 ppm.

EXAMPLE 9

[0246] Intermediate 9A: 2,2-Bis-(4-chlorophenyl)-N-methyl-ethylamine

[0247] Intermediate 9A was prepared from 2,2-bis-(4-chlorophenyl)-N-methylacetamide using Method II, step II. ¹HNMR 400 MHz (C₆D₆) δ (ppm): 2.26 (3H, s, NCH₃), 2.89 (2H, d, J=7.1 Hz, CH₂), 3.87 (1H, t, J=7.1 Hz, CH), 6.86 (4H, d, J=8.3 Hz, aromatics) and 7.19 (4H, d, J=8.3 Hz, aromatics).

[0248] Intermediate 9B: N-{2,2-Bis-(4-chlorophenyl)-ethyl}-N-methylacetamide

[0249] Intermediate 9B was prepared from Intermediate 9A using Method VIII. Solid: mp 103-104° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm) mixture of rotamers; 1.92 (3H, s, COCH₃), 2.63 and 2.78 (3H, 2 s, NCH₃), 3.79 and 3.85 (2H, 2d, J=7.6 Hz and J=8.0 Hz, CH₂), 4.10 and 4.30 (1H, 2t, J=7.6 Hz and J=8.0 Hz, CH), 7.03-7.25 (8H, m, aromatics). Anal. Calcd for C₁₇H₁₇Cl₂NO: C 63.37, H 5.32, N 4.35. Found: C 63.09, H 5.34, N 4.29. MS (ESI⁺) (m/z): 322 (M+H).

[0250] Intermediate 9C: 3-{[2,2-Bis-(4-chloro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid Methyl Ester

[0251] Intermediate 9C was prepared from Intermediate 9B using Method IX. ¹HNMR 400 MHz (CDCl₃) δ (ppm) mixture of rotamers; 2.81 and 2.88 (3H, 2 s, NCH₃), 3.92 and 3.93 (3H, 2 s, OCH₃), 3.99 and 4.06 (2H, 2d, J=7.6 Hz and J=8.1 Hz, CH₂), 4.23 and 4.45 (1H, 2t, J=7.6 Hz and J=8.1 Hz, CH), 5.95 and 6.17 (1H, 2 s, CH), 7.16-7.37 (8H, m, aromatics). MS (ESI⁺) (m/z): 408 (M+H).

[0252] Compound 9: 3-{[2,2-Bis-(4-chloro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0253] Compound 9 was prepared from Intermediate 9C using Method XI. ¹HNMR 400 MHz (CDCl₃) δ (ppm) mixture of rotamers; 2.78 and 2.84 (3H, 2 s, NCH₃), 3.95 and 4.02 (2H, 2 d, J=8.1 Hz and J=8.3 Hz, CH₂), 4.18 and 4.38 (1H, 2t, J=8.1 Hz and J=8.3 Hz, CH), 6.0 and 6.2 (1H, 2 s, CH), 7.1-7.31 (8H, m, aromatics). HRMS (ESI⁻) calculated for C₁₉H₁₆Cl₂NO₄ [M−H]⁻: 392.0456: found: 392.0475, δ-4.8 ppm.

EXAMPLE 10

[0254] Intermediate 10A: N-(2-Chloro-benzyl)-N-methyl-acetamide

[0255] 2-Chlorobenzyl bromide (1.37 g, 6.67 mmol) was dissolved in 5 ml of THF. To this was added 5 ml of 40% (aq.) methylamine and the resulting mixture stirred 15 min. The reaction mixture was transferred to a separatory funnel, diluted with 100 ml H₂O and extracted with 100 ml of ethyl acetate. The organic solution was washed with brine, dried over Na₂SO₄ then filtered and the solvent removed to yield 1.21 g oil. The crude product was purified by column chromatography (5×6.5 cm SiO₂, 2-10% EtOH/CH₂Cl₂) to yield 710 mg (68% yield) oil. LC/MS (M+H) calcd for C₈H₁₁ClN: 156.06; found: 155.99.

[0256] The amine (710 mg, 4.6 mmol) synthesized above was dissolved in 30 ml CH₂Cl₂. Satd. (aq.) NaHCO₃ was added followed by CH₃COCl (0.36 ml, 5.0 mmol) and the resulting mixture stirred for 1 h. The organic layer was separated, washed with brine dried over Na₂SO₄ then filtered and the solvent removed to yield 900 mg (>99% yield) oil as a pure product. LC/MS (M+H) calcd for C₁₀H₁₃ClNO: 198.06; found: 198.02. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.10 (s), 2.19 (s), 2.97 (s), 4.59 (s), 4.73 (S), 7.10-7.41 (overlapping m, 4). ¹³C NMR (125 MHz, CDCl₃) δ: 21.33, 21.82, 34.06, 36.03, 48.06, 52.22, 126.79, 127.10, 127.36, 128.54, 128.83, 129.10, 129.57, 129.91, 132.84, 133.59, 133.96, 134.67, 170.99, 171.41. LC/MS (M+H) calcd for C₁₀H₁₃ClNO: 198.06; found: 198.02. Anal calcd for C₁₀H₁₂ClNO: C, 60.76; H, 6.11; N, 7.08; Cl, 17.93; found: C, 60.53; H, 6.15; N, 7.04; Cl, 17.81.

[0257] Intermediate 10B: 3-[(2-Chloro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0258] Intermediate 10A (1.96 g, 9.92 mmol) was dissolved in 20 ml of anhydrous THF under an N₂ atmosphere then cooled to −78° C. To this was added 30 ml of 1M LiHMDS (lithium bis(trimethylsilyl)amide) and the reaction mixture stirred for 20 min. at which point dimethyl oxalate (1.76 g, 14.9 mmol) dissolved in 8 ml of THF was added. The reaction was allowed to continue at −78° C. for 20 min. then warmed to 0° C. and stirred an additional 45 min. 1 N HCl was added and the resulting mixture extracted with EtOAc. The organic solution was washed with brine, dried over Na₂SO₄ then filtered and the solvent removed to yield 2.80 g oil. The crude product was purified by reverse phase preparative HPLC (C₁₈, MeOH/H₂O (0.1% TFA)-gradient) to yield 382 mg (14% yield) oil. LC/MS (M+H) calcd for C₁₃H₁₅NO₄Cl: 284.06; found 284.01. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.06 (s), 3.07 (s), 3.85 (s), 3.91 (s), 4.68 (s), 4.81 (s), 6.19 (s), 6.34 (s), 7.07-7.44 (overlapping m, 4).

[0259] Compound 10: 3-[(2-Chloro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0260] Compound 10 was prepared from Intermediate 10B using Method X. More specifically, to a solution of Intermediate 10B (95 mg, 0.33 mmol) dissolved in 0.4 ml of MeOH was added 0.4 ml of 1N NaOH. After stirring for 1 h, 0.4 ml of 1N HCL was added and the resulting mixture extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄ then filtered and the solvent removed to yield 100 mg oil. The crude product was purified by reverse phase preparative HPLC (C₁₈, MeOH/H₂O (0.1%TFA)) to yield 47 mg (52% yield) solid. mp=84-86° C. LC/MS (M+H) calcd for C₁₂H₁₃ClNO₄: 270.05; found: 269.96. HRMS (M+H) calcd for C₁₂H₁₃ClNO₄: 270.0533; found: 270.0534. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.08 (s), 4.69 (s), 4.82 (s), 6.27 (s), 6.41 (s), 7.06-7.45 (overlapping m, 4). ¹³C NMR (125 MHz, CDCl₃) δ: 34.00, 35.36, 48.34, 51.18, 93.44, 127.20, 127.33, 127.48, 128.97, 129.10, 129.35, 129.83, 130.08, 132.70, 133.02, 133.33, 133.62, 159.11, 159.22, 164.65, 164.73, 171.21, 171.60.

EXAMPLE 11

[0261] Intermediate 11A; N,N-bis-(4-fluoro-benzyl)-acetamide

[0262] To 4-flourobenzylamine (1.17 g, 9.4 mmol) dissolved in 5 mL of THF was added 4-fluorobenzyl-bromide (0.88 g, 4.7 mmol) dropwise. The reaction was stirred overnight resulting in the formation of a white solid. After filtering off the solid solvent was removed to yield 1.08 g crude di-(4-fluorobenzyl) amine. To this was added 19 mL of CH₂Cl₂ and 19 mL of saturated (aq.) NaHCO₃. Acetyl chloride (0.67 mL, 9.4 mmol) was added to the rapidly stirring mixture and the reaction allowed to proceed overnight. The mixture was diluted with CH₂Cl₂, transferred to a separatory funnel. The organic layer was separated, washed with satd (aq.) NaCl, dried over Na₂SO₄ and the solvent removed to yield 1.01 g oil. The product was purified by column chromatography (4×7 cm SiO₂, 20-40% EtOAc/Hexanes) to yield 603 mg (55% yield) oil. LC/MS (M+H) calcd for C₁₄H₁₄NF₂: 276.12, found: 276.13. HRMS (M+H) calcd for C₁₄H₁₄NF₂: 276.1200, found: 276.1192. Anal calcd for C₁₆H₁₅F₂NO: C, 69.80; H, 5.49; N, 5.08; found: C, 59.53; H, 5.41; N, 5.06. ¹H NMR (500 MHz, DMSO) δ: 2.10 (s, 3), 4.45 (s, 2), 4.49 (s, 2), 7.18-7.27 (m, 8). ¹³C NMR (125 MHz, DMSO) 6; 21.34, 47.04, 50.04, 114.90, 115.07, 115.27, 115.45, 128.51, 128.58, 129.57, 129.64, 133.32, 133.34, 133.86, 133.89, 160.25, 160.33, 162.17, 162.27, 170.22.

[0263] Intermediate 11B: 3-[Bis-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0264] Intermediate 11B was prepared from Intermediate 11A by the same method that Intermediate 10B was prepared from Intermediate 10A. Solid, mp=117-118° C. LC/MS (M+H) calcd for C₁₉H₁₈F₂NO₄: 362.11, found: 362.03. HRMS (M+H) calcd for C₁₉H₁₈F₂NO₄: 362.1204, found: 362.1187. Anal. calcd for C₁₉H₁₇NO₄F₂: C, 63.15; H, 4.74; N, 3.87; found: C, 62.97; H, 4.72; N, 3.81. ¹H NMR (500 MHz, CDCl₃) δ: 3.87 (s, 3), 4.46 (s, 2), 4.58 (s, 2), 6.32 (s, 1), 7.00-7.26 (m, 8). ¹³C NMR (125 MHz, CDCl₃) δ: 47.34, 49.35, 53.03, 93.34, 115.56, 115.83, 116.00, 116.18, 128.45, 128.52, 130.03, 130.10, 131.09, 131.93, 131.96, 160.29, 161.44, 161.51, 163.10, 163.41, 163.47, 171.36.

[0265] Compound 11: 3-[Bis-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0266] Compound 11 was prepared from Intermediate 11B by Method XI. Solid mp>147° C. (decomposition). LC/MS (M+H) calcd for C₁₈H₁₆F₂NO₄: 348.10, found 347.98. HRMS (M−H) calcd for C₁₈H₁₄F₂NO₄: 346.089, found 346.088. ¹H NMR (500 MHz, DMSO) δ: 4.61 (s, 2), 4.67 (s, 2), 6.25 (s, 1), 7.12-7.35 (overlapping m). ¹³C NMR (125 MHz, DMSO) δ: 47.94, 49.49, 93.27, 115.11, 115.28, 115.38, 115.55, 128.46, 128.52, 129.88, 129.94, 132.76, 132.78, 132.93, 132.96, 10.35, 163.27, 171.25.

EXAMPLE 12

[0267] Intermediate 12A: N-(2-bromo-benzyl)-N-methyl-acetamide

[0268] Intermediate 12A was prepared from ortho-bromobenzyl bromide by Method V. Anal calcd for C₁₀H₁₂BrNO: C, 49.60; H, 4.99; N, 5.78; Br, 33.00; found: C, 49.40; H, 4.95; N, 5.75; Br, 32.98. LC/MS (M+H) calcd for C₁₀H₁₃BrNO: 242.02; found: 243.96. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.09 (s), 2.19 (s), 2.98 (s), 2.99 (s), 4.55 (s), 4.71 (s), 7.08-7.60 (overlapping m, 4). ¹H NMR (300 MHz, DMSO, T=393 K) δ: 2.06 (s, 3), 2.92 (s, 3), 4.58 (s, 2), 7.21 (m, 2), 7.37 (m, 1), 7.60 (d, 1, J=8).

[0269] Intermediate 12B: 3-[(2-Bromo-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0270] Intermediate 12B was prepared from Intermediate 12A using Method IX. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.06 (s), 3.07 (s), 3.85 (s), 3.91 (s), 4.65 (s), 4.79 (s), 7.17-7.35 (overlapping m, 4).

[0271] Compound 12: 3-[(2-Bromo-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0272] Compound 12 was prepared from Intermediate 12B using Method X. HRMS (M+H) calcd for C₁₂H₁₃BrNO₄: 314.0028; found: 314.0023. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.08 (s, 3), 4.66 (s), 4.80 (s), 6.25 (s), 6.42 (s), 7.04-7.63 (overlapping m, 4). ¹³C NMR (125 MHz, CDCl₃) δ: 34.09, 35.37, 50.85, 53.70, 93.21, 122.84, 123.59, 127.17, 127.97, 128.11, 128.77, 129.38, 129.63, 133.17, 133.40, 134.13, 134.82, 159.00, 159.14, 171.22, 171.64.

EXAMPLE 13

[0273] Intermediate 13A: N-benzyl-N-phenethyl-acetamide

[0274] N-benzyl-2-phenethylamine (2.2 g, 10 mmol) was dissolved in 7 mL of CH₂Cl₂. To this was added 7 mL of satd (aq.) NaHCO₃ followed by acetyl chloride (0.88 g, 11 mmol) and the resulting mixture stirred for 40 min. The organic layer was separated, dried over Na₂SO₄ filtered and the solvent removed to yield 2.60 g (100%) oil. LC/MS (M+H) calcd for C₁₇H₂₀NO: 254.15; found: 254.07. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃), δ: 2.04 (br s), 2.14 (br s), 2.81 (br m), 2.87 (br m), 3.44 (br m), 3.58 (br m), 4.36 (s), 4.62 (s), 7.11-7.36 (overlapping m, 10). ¹³C NMR (125 MHz, CDCl₃) δ: 21.19, 21.80, 33.99, 34.87, 48.18, 48.28, 49.49, 52.75, 126.34, 126.81, 127.44, 127.65, 128.18, 128.52, 128.64, 128.73, 128.80, 128.85, 128.94, 136.74, 137.56, 138.17, 139.24, 170.81, 171.07.

[0275] Intermediate 13B: 3-(Benzyl-phenethyl-carbamoyl)-2-hydroxy-acrylic Acid Methyl Ester

[0276] Intermediate 13B was prepared from Intermediate 13A using Method IX. LC/MS (M+H) calcd for C₂₀H₂₂NO₄: 340.03; found: 340.15. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.84 (t, J=7), 2.90 (t, J=7), 3.52 (t, J=7), 3.63 (t, J=7), 3.86 (s), 3.90 (s), 4.41(s), 4.56 (s), 6.22 (s), 6.26 (s), 7.13-7.37 (overlapping m, 10). ¹³C NMR (125 MHz, CDCl₃) δ: 33.94, 35.38, 48.40, 48.94, 51.84, 52.97, 93.72, 126.62, 126.65, 126.97, 127.81, 128.02, 128.05, 128.67, 128.77, 128.83, 128.90, 129.03, 135.84, 136.56, 137.64, 138.64, 159.52, 159.80, 163.31, 170.88, 171.28.

[0277] Compound 13: 3-(Benzyl-phenethyl-carbamoyl)-2-hydroxy-acrylic Acid

[0278] Compound 13 was prepared from Intermediate 13B using Method X. LC/MS (M+H) calcd for C₁₉H₂₀NO₄: 326.14; found: 326.01. HRMS (M−H) calcd for C₁₉H₁₈NO₄: 324.1236; found: 324.1234. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.85 (t, J=7), 2.90 (t, J=7), 3.54 (t, J=7), 3.65 (t, J=7), 4.41 (s), 4.56 (s), 6.26 (s), 6.33 (s), 7.11-7.40 (overlapping m, 10). ¹³C NMR (125 MHz, CDCl₃) δ: 33.91, 35.30, 48.59, 49.05, 49.10, 51.97, 93.76, 93.86, 126.69, 128.09, 128.28, 128.72, 128.78, 128.80, 128.88, 128.97, 129.09, 135.55, 136.29, 137.45, 138.49, 158.84, 159.27, 165.08, 165.15, 170.85, 171.26.

EXAMPLE 14

[0279] Intermediate 14A: N,N-dibenzyl-acetamide

[0280] Intermediate 14A was prepared from dibenzylamine by the same method as Intermediate 12A. LC/MS (M+H) calcd for C₁₆H₁₈NO: 240.14; found: 240.03. ¹H NMR (500 MHz, CDCl₃) δ: 3.23 (s, 3), 4.47 (s, 2), 4.61 (s, 2), 7.16-7.39 (overlapping m, 10). ¹³C NMR (125 MHz, CDCl₃) δ: 21.70, 48.02, 50.78, 126.42, 127.46, 127.68, 128.34, 128.63, 129.01, 136.41, 137.31, 171.22.

[0281] Intermediate 14B: 3-Dibenzylcarbamoyl-2-hydroxy-acrylic Acid Methyl Ester

[0282] Intermediate 14B was prepared from Intermediate 14A using Method IX. LC/MS (M+H) calcd for C₁₉H₂₀NO₄: 326.14; found: 326.01. ¹H NMR (500 MHz, CDCl₃) δ: 3.87 (s, 3), 4.51 (s, 2), 4.64 (s, 2), 6.36 (s, 1), 7.17-7.40 (overlapping m, 10). ¹³C NMR (125 MHz, CDCl₃) δ: 48.02, 49.95, 53.00, 93.62, 126.78, 127.85, 128.08, 128.13, 128.25, 128.77, 128.85, 129.00, 129.10, 135.50, 136.24, 160.05, 163.22, 171.43.

[0283] Compound 14: 3-Dibenzylcarbamoyl-2-hydroxy-acrylic Acid

[0284] Compound 14 was prepared from Intermediate 14B using Method X. LC/MS (M+H) calcd for C₁₈H₁₈NO₄: 312.12; found: 312.07. HRMS (M−H) calcd for C₁₈H₁₆NO₄: 310.1079; found: 310.1075. ¹H NMR (500 MHz, CDCl₃) δ: 4.52 (s, 2), 4.66 (s, 2), 6.43 (s, 1), 7.16-7.43 (overlapping m, 10). ¹³C NMR (125 MHz, CDCl₃) δ: 48.30, 50.07, 93.24, 126.77, 127.98, 128.20, 128.27, 128.90, 129.15, 135.12, 135.90, 159.35, 164.50, 171.43.

EXAMPLE 15

[0285] Intermediate 15A: N-(5-Chloro-benzo[b]thiophen-3-ylmethyl)-N-methyl-acetamide

[0286] Intermediate 15A was prepared from 3-(bromomethyl)-5-chlorobenzothiophene by Method V. LC/MS (M+H) calcd for C₁₂H₁₃NOClS: 254.04; found: 253.92. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.17 (s, 3), 2.93 (s), 3.05 (s), 4.70 (s), 4.79 (s), 7.22-7.88 (overlapping m, 5). ¹³C NMR (125 MHz, CDCl₃) δ: 1.26, 21.92, 34.17, 35.27, 44.22, 49.43, 120.77, 122.04, 123.76, 124.18, 125.16, 125.42, 126.79, 131.85, 138.66, 139.30, 170.78.

[0287] Intermediate 15B: 3-[(5-Chloro-benzo[b]thiophen-3-ylmethyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0288] Intermediate 15B was prepared from Intermediate 15A using Method IX. LC/MS (M+H) calcd for C₁₅H₁₅NO₄ClS: 340.04; found: 339.89. HRMS (M+H) calcd for C₁₅H₁₅NO₄ClS: 340.0410; found: 340.0410. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.03 (s), 3.13 (s), 3.85 (s), 3.90, 4.77 (s), 4.87 (s), 6.28 (s), 6.30 (s), 7.23-7.86 (overlapping m, 4).

[0289] Compound 15: 3-[(5-Chloro-benzo[b]thiophen-3-ylmethyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0290] Compound 15 was prepared from Intermediate 15B using Method X. LC/MS (M+H) calcd for C₁₄H₁₃NO₄ClS: 326.03; found: 326.08. HRMS (M−H) calcd for C₁₄H₁₁NO₄ClS: 324.0097; found: 324.0104. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, DMSO) δ: 3.05 (s), 4.85 (s), 4.97 (s), 6.27 (s), 6.30 (s), 7.41-8.07 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.68, 34.46, 43.62, 47.54, 93.00, 93.32, 121.33, 121.38, 121.61, 124.55, 124.64, 124.71, 125.55, 128.15, 129.41, 129.52, 130.79, 131.21, 138.37, 138.45, 138.99, 139.05, 160.02, 160.12, 163.38, 163.45, 170.50, 171.05.

EXAMPLE 16

[0291] Intermediate 16A: N-(4-fluoro-benzyl)-N-methyl-acetamide

[0292] Intermediate 16A was prepared from 4-fluorobenzyl bromide by Method IV. LC/MS (M+H) calcd for C₁₀H₁₃FNO: 182.09; found: 182.10. HRMS (M+H) calcd for C₁₀H₁₄NFNO; 182.0891; found: 182.0979. ¹H NMR (500 MHz, DMSO) δ: 2.04 (s), 2.05 (s), 2.77 (s), 2.90 (s), 4.46 (s), 4.53 (s), 7.13-7.28 (m, 4). ¹³C NMR (125 MHz, DMSO) δ: 21.16, 21.47, 32.85, 35.24, 48.81, 52.40, 114.97, 115.14, 115.30, 115.47, 128.52, 128.59, 129.38, 129.44, 133.58, 133.60, 134.01, 134.03, 160.23, 160.33, 162.16, 162.26, 169.70, 169.84.

[0293] Intermediate 16B: 3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0294] Intermediate 16B was prepared from Intermediate 16A using Method IX. HRMS (M+H) calcd for C₁₃H₁₅NO₄F: 268.0985; found: 268.0983. Anal calcd for C₁₃H₁₄NO₄F: C, 58.42; H, 5.28; N, 5.24; found: C, 58.48; H, 5.21; N, 5.26. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. LC/MS (M+H) calcd for C₁₃H₁₅FNO₄: 268.09, found: 268.15. ¹H NMR (500 MHz, CDCl₃) δ: 3.00 (s, 3), 3.86 (s), 3.89 (s), 4.55 (s), 4.61 (s), 6.29 (s) 6.31, 7.00-7.24 (overlapping m, 4). ¹³ C NMR δ: 33.43, 34.79, 49.97, 52.63, 52.97, 93.27, 93.55, 115.63, 115.80, 115.95, 116.13, 128.36, 128.42, 129.71, 129.78, 131.32, 132.03, 159.70, 161.40, 163.25, 163.35, 170.93, 171.16.

[0295] Compound 16: 3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0296] Compound 16 was prepared from Intermediate 16B using Method XI. HRMS (M−H) calcd for C₁₂H₁₁NO₄F: 252.0672; found: 252.0666. Anal calcd for C₁₂H₁₂NO₄F: C, 56.91; H, 4.77; N, 5.53; found: C, 57.22; H, 4.78; N, 5.56. LC/MS (M+H) calcd for C₁₂H₁₃FNO₄: 254.08, found: 254.05. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ 3.02 (s, 3), 4.57 (s), 4.63 (s), 6.36 (s), 6.39, 7.02-7.26 (overlapping m, 4).

EXAMPLE 17

[0297] Intermediate 17A: N-benzyl-N-methyl-acetamide

[0298] Intermediate 17A was prepared from N-methyl-benzylamine using Method IV. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.20 (s), 2.95 (s), 2.97 (s), 4.56 (s), 4.62 (s), 7.19-7.41 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.42, 21.80, 33.82, 35.58, 50.68, 54.29, 126.33, 127.41, 127.70, 128.07, 128.63, 128.99, 136.46, 137.26, 170.88, 171.19.

[0299] Intermediate 17B: 3-(Benzyl-methyl-carbamoyl)-2-hydroxy-acrylic Acid Methyl Ester

[0300] Intermediate 17B was prepared from Intermediate 17A using Method IX. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.02 (s), 3.86 (s), 3.90 (s), 4.60 (s), 4.66 (s), 6.31 (s), 6.34 (s), 7.18-7.40 (overlapping m).

[0301] Compound 17: 3-(Benzyl-methyl-carbamoyl)-2-hydroxy-acrylic Acid

[0302] Compound 17 was prepared from Intermediate 17B using Method X. HRMS (M−H) calcd for C₁₂H₁₂NO₄: 234.0766; found: 234.0765. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.02 (s), 3.04 (s), 4.59 (s), 4.67 (s), 6.36 (s), 6.40 (s), 7.17-7.39 (overlapping m).

EXAMPLE 18

[0303] Intermediate 18A: N-(2-Chloro-benzyl)-N-[2-(4-fluoro-phenyl)-ethyl]-acetamide

[0304] Intermediate 18A was prepared from 2(-4-fluorophenyl)-ethylamine and 2-chlorobenzylbromide using Method VI. LC/MS (M+H) calcd for C₁₇H₁₈ClFNO: 306.10; found: 306.00. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.05(s), 2.10(s), 2.84(m), 3.44(m), 3.55(m), 4.46(s), 4.77(s), 6.99(m), 7.13(m), 7.22(m), 7.38(m).

[0305] Intermediate 18B: 3-{2-Chloro-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-carbamoyl}-2-hydroxy-acrylic Acid Methyl Ester

[0306] Intermediate 18B was prepared from Intermediate 18A using Method IX. HRMS (M+H) calcd for C₂₀H₂₀NO₄ClF: 392.1065; found: 392.1053. Anal calcd for C₂₀H₁₉NO₄ClF: C, 61.30; H, 4.88; N, 3.57; found: C, 61.33; H, 4.86; N, 3.50. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.87(m), 3.53(m), 3.60(m), 3.85(s), 3.91(s), 4.53(s), 4.74(s), 6.14(s), 6.20(s), 6.97-7.42(overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.12, 34.62, 46.17, 48.55, 49.36, 49.52, 52.98, 53.01, 93.43, 115.41, 115.58, 115.68, 115.85, 127.36, 127.41, 127.44, 129.10, 129.26, 129.39, 129.73, 129.98, 130.21, 130.27, 130.33, 132.96, 133.19, 133.59, 133.98, 159.71, 160.04, 160.77, 160.95, 162.72, 162.91, 163.20, 171.08, 171.64.

[0307] Compound 18: 3-{(2-Chloro-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-carbamoyl}-2-hydroxy-acrylic Acid

[0308] Compound 18 was prepared from Intermediate 18B using Method X. HRMS (M−H) calcd for C₁₉H₁₆NO₄ClF: 376.0752; found: 376.0761. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.87(m), 3.53(dd, J=7, 7), 3.62(dd, J=7, 9), 4.55(s), 4.75(s), 6.23(s), 6.27(s), 6.97-7.43 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.07, 34.53, 46.32, 48.67, 49.40, 49.61, 93.27, 115.46, 115.63, 115.75, 115.92, 127.40, 127.44, 129.25, 129.42, 129.45, 129.80, 130.08, 130.20, 130.27, 130.29, 130.35, 132.82, 133.02, 133.64, 133.67, 158.90, 159.30, 160.80, 160.99, 162.75, 162.95, 171.06, 171.61.

EXAMPLE 19

[0309] Intermediate 19A: N-(2-Chlorobenzyl)-N-(4-fluorobenzyl)-acetamide

[0310] Intermediate 19A was prepared from 2-chlorobenzylamine and 4-fluorobenzylbromide using Method VI. LCMS (M+H) calcd for C₁₆H₁₆FNO: 292.08; found: 292.01. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.15(s), 2.24(s), 4.47(s), 4.51(s), 4.56(s), 4.73(s), 6.97-7.40 (overlapping m, 8). ¹³C NMR (125 MHz, CDCl₃) δ: 21.52, 21.62, 45.86, 48.04, 49.09, 50.93, 115.40, 115.57, 115.82, 115.99, 126.92, 127.10, 127.33, 127.97, 128.04, 128.70, 128.93, 129.50, 129.58, 129.98, 130.02, 130.09, 131.99, 132.02, 132.91, 132.93, 132.99, 133.65, 133.67, 134.54, 161.30, 163.25, 171.29, 171.52.

[0311] Intermediate 19B: 3-[(2-Chloro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0312] Intermediate 19B was prepared from Intermediate 19A using Method IX. HRMS (M+H) calcd for C₁₉H₁₈ClFNO₄: 378.0908; found: 378.0908. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.85(s), 3.88(s), 4.53(s), 4.60(s), 4.61(s), 4.78(s), 6.19(s), 6.37(s), 7.00-7.42 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 45.88, 48.06, 48.08, 50.07, 53.00, 53.04, 53.45, 93.29, 93.36, 115.63, 115.80, 115.92, 116.10, 127.29, 127.41, 128.42, 128.48, 129.09, 129.24, 129.26, 129.77, 130.03, 130.07, 130.14, 131.16, 131.92, 132.81, 133.05, 133.58, 133.66, 160.29, 160.31, 161.47, 163.05, 163.11, 163.43, 171.62, 171.80.

[0313] Compound 19: 3-[(2-Chloro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0314] Compound 19 was prepared from Intermediate 19B using Method X. HRMS (M−H) calcd for C₁₈H₁₄NO₄ClF: 362.0595; found: 362.0604. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 4.54(s), 4.60(s), 4.62(s), 4.79(s), 6.27(s), 6.44(s), 7.01-7.42 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 46.09, 48.17, 48.27, 50.15, 93.43, 93.56, 115.70, 115.87, 116.00, 116.17, 127.26, 127.32, 127.44, 128.42, 128.49, 129.23, 129.30, 129.40, 129.83, 130.11, 130.18, 130.86, 130.88, 131.61, 131.63, 132.48, 133.08, 133.29, 133.69, 159.29, 159.35, 161.53, 164.31, 171.55, 171.71.

EXAMPLE 20

[0315] Intermediate 20A: N-(5-Chloro-benzo[b]thiophen-3-ylmethyl)-N-[2-(4-fluoro-phenyl)-ethyl]-acetamide

[0316] Intermediate 20A was prepared from 2-(4-fluoro-phenyl)-ethylamine and 3-bromomethyl-5-chloro-benzo{b}thiophene using Method VI. HRMS (M+H) calcd for C₁₉H₁₈NOClFS: 362.0782; found: 362.0776. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.05 (s), 2.16 (s), 2.73 (t, J=8), 2.87 (t, J=8), 3.42 (t, J=8), 3.63 (t, J=8), 4.52 (s), 4.79 (s), 6.96-7.82 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.37, 21.68, 33.40, 34.23, 41.90, 47.94, 48.48, 49.26, 115.31, 115.47, 115.65, 115.82, 120.74, 121.88, 123.86, 124.19, 124.42, 125.22, 125.45, 126.84, 130.14, 130.20, 130.22, 130.28, 130.90, 130.96, 131.22, 132.01, 133.68, 133.71, 134.58, 134.60, 138.27, 138.64, 139.18, 139.31, 160.85, 162.80, 170.58, 170.94.

[0317] Intermediate 20B: 3-{(5-Chloro-benzo[b]thiophen-3-ylmethyl)-[2-(4-fluoro-phenyl)-ethyl]-carbamoyl}-2-hydroxy-acrylic Acid Methyl Ester

[0318] Intermediate 20B was prepared from Intermediate 20A using Method IX. HRMS (M+H) calcd for C₂₂H₁₉NO₄SFCl: 448.0786; found: 448.0777. Anal calcd for C₂₂H₁₈NO₄SFCl: C, 58.99; H, 4.27; N, 3.12; found: C, 59.36; H, 4.22; N, 3.08. ¹H NMR and ¹³C NMR show a Mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.75(t, J=7), 2.90(dd, J=8, 8), 3.51(t, J=7), 3.68(dd, J=8, 8), 3.84(s), 3.91(s), 4.57(s), 4.75(s), 6.18(s), 6.21(s), 6.97-7.80 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.34, 34.68, 42.60, 46.91, 48.65, 53.01, 53.04, 93.33, 93.64, 115.48, 115.65, 115.69, 115.75, 115.86, 115.92, 120.76, 121.67, 123.97, 124.22, 125.40, 125.56, 127.35, 130.21, 130.28, 130.91, 131.04, 131.12, 133.19, 134.03, 138.16, 138.65,139.03, 139.11, 159.82, 160.18, 160.96, 162.92, 163.09, 163.18, 170.83, 171.40.

[0319] Compound 20: 3-{(5-Chloro-benzo[b]thiophen-3-ylmethyl)-[2-(4-fluoro-phenyl)-ethyl]-carbamoyl}-2-hydroxy-acrylic Acid

[0320] Compound 20 was prepared from Intermediate 20B using Method X. HRMS (M−H) calcd C₂₁H₁₆NO₄SClF: 432.0473; found: 432,0485. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.75(t, J=7), 2.90(dd, J 7, 7), 3.52(t, J=7), 3.69(dd, J=7), 4.59(s), 4.76(s), 6.26(s), 6.30(s), 6.98-7.81(overlapping m).

EXAMPLE 21

[0321] Intermediate 21A: N-(2-Chloro-benzyl)-N-[2-(4-fluoro-phenyl)-ethyl]-acetamide

[0322] Intermediate 21A was prepared from 4-fluorobenzylamine and 5-chloro-3-bromomethyl-benzo[b]thiophene using Method VI. HRMS (M+H) calcd C₁₈H₁₆ClFNOS: 348.0652; found: 348.0619. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.24(s), 4.41(s), 4.59(s), 4.65(s), 4.79(s), 6.98-7.33(overlapping m), 7.54(m), 7.74-7.82(overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.56, 21.81, 41.35, 46.25, 47.94, 49.95, 115.47, 115.64, 115.93, 116.10, 120.79, 122.00, 123.77, 124.16, 124.37, 125.18, 125.45, 127.30, 127.95, 128.02, 129.98, 130.04, 130.77, 130.92, 131.58, 131.74, 131.77, 133.06, 138.33, 138.60, 139.20, 139.35, 161.32, 163.28, 170.93, 171.15.

[0323] Intermediate 21B: 3-[(5-Chloro-benzo[b]thiophen-3-ylmethyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0324] Intermediate 21B was prepared from Intermediate 21A using Method IX. HRMS (M+H) calcd for C₂₁H₁₈NO₄SFCl: 434.0629; found: 434.0626. Anal. calcd for C₂₁H₁₇NO₄SFCl: C, 58.13; H, 3.94; N, 3.22; found: C, 58.42; H, 3.95; N, 3.02. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) 6:3.85(s), 3.88(s), 4.49(s), 4.66(s), 4.69(s), 4.84(s), 6.28(s), 6.34(s), 7.01-7.81(overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 41.50, 45.21, 47.98, 49.17, 53.04, 53.06, 93.25, 93.40, 115.73, 115.90, 116.01, 116.18, 120.81, 121.76, 123.88, 124.19, 125.35, 125.56, 127.74, 128.35, 128.42, 129.79, 129.99, 130.05, 130.43, 130.93, 130.96, 131.03, 131.07, 131.98, 138.22, 138.62, 139.09, 139.12, 160.42, 160.45, 161.50, 162.99, 163.07, 163.46, 171.31, 171.53.

[0325] Compound 21: 3-[(5-Chloro-benzo[b]thiophen-3-ylmethyl)₇(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0326] Compound 21 was prepared from Compound 21B using Method X. HRMS (M−H) calcd for C₂₀H₁₄NO₄SClF: 418.0316; found: 418.0323. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 4.50(s), 4.67(s), 4.74(s), 4.85(s), 6.36(s), 6.41(s), 7.01-7.83 (overlapping m).

EXAMPLE 22

[0327] Intermediate 22A: N-[2-(4-Fluoro-phenyl)-ethyl]-N-methyl-acetamide

[0328] 2-(4-Fluoro-phenyl)-ethylamine (1.3 g, 9.33 mmol) was dissolved in 37 mL of CH₂Cl₂. To this was added 37 mL of satd NaHCO₃follwed by acetyl chloride (2.1 mL, 30.9 mmol). The resulting mixture was stirred 6 hours. The organic layer was separated, washed with satd NaCl, dried over Na₂SO₄, and the solvent removed under vacuum to yield 280 mg of N-[2-(fluoro-phenyl)-ethyl]-acetamide.

[0329] N-[2-(fluoro-phenyl)-ethyl]-acetamide (270 mg, 1.5 mmol) was dissolved in 7.5 mL of toluene to this was added 120 mg of 60% NaH (mineral oil) and MeI (0.12 mL, 1,95 mmol). The resulting mixture was stirred overnight. The solution was diluted with EtOAc, washed with satd NaCl, dried over Na₂SO₄ and the solvent removed under vacuum. The crude product was purified by flash column chromatography (SiO₂, CH₂Cl₂/EtOH) to yield 230 mg (79% yield) of N-[2-(4-fluoro-phenyl)-ethyl]-N-methyl-acetamide. HRMS (M+H) calcd for C₁₁H₁₅FNO: 196.1138; found: 196.1137. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.85 (s), 2.06 (s), 2.81 (m), 2.88 (s), 2.93 (s), 3.48 (m), 3.55 (m), 6.96-7.18 (overlapping m).

[0330] Intermediate 22B: 3-{[2-(4-Fluoro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid Methyl Ester

[0331] Intermediate 22B was prepared from Intermediate 22A using Method IX. HRMS (M+H) calcd for C₁₄H₁₇NO₄F: 282.1142; found: 282.1135. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.87(m), 2.95(s), 3.57(t, J=7), 3.63(dd, J=7, 7), 3.87(s), 3.88(s), 6.05(s), 6.20(s), 6.98(m), 7.15(m). ¹³C NMR (125 MHz, CDCl₃) δ: 32.90, 34.02, 34.31, 36.18, 49.96, 51.76, 52.91, 52.94, 93.42, 93.60, 115.40, 115.57, 115.68, 115.85, 130.17, 130.24, 130.31, 133.25, 134.16, 134.19, 159.06, 159.48, 160.74, 160.95, 162.69, 162.90, 163.31, 163.37, 170.74.

[0332] Compound 22: 3-{[2-(4-Fluoro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0333] Compound 22 was prepared from Intermediate 22A using Method XI. HRMS (M−H) calcd for C₁₃H₁₃NO₄F: 266.0829; found: 266.0823. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.89(m), 2.97(s), 2.98(s), 3.59(t, J=7), 3.65(dd, J=7, 7), 6.13(s), 6.27(s), 6.99(m), 7.14(m). ¹³C NMR (125 MHz, CDCl₃) δ: 32.86, 34.20, 36.26, 50.14, 51.88, 93.33, 115.46, 115.63, 115.75, 115.92, 130.17, 130.24, 130.33, 133.032, 133.96, 158.43, 159.11, 165.03, 170.72.

EXAMPLE 23

[0334] Intermediate 23A: N-(4-Fluoro-benzyl)-N-(1-phenyl-ethyl)-acetamide

[0335] Intermediate 23A was prepared from 4-fluorobenzylamine and (1-bromo-ethyl)-benzene using Method VI. HRMS (M+H) calcd for C₁₇H₁₉FNO: 272.1451; found: 272.1454. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.42(d, J=7), 1.49(d, J=7), 2.05(s), 2.29(s), 3.99(d, J=15), 4.18(d, J=18), 4.37(d, J=18), 4.80(d, J=15), 5.17(m), 6.18(m), 6.86-7.35 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 16.96, 19.00, 22.17, 22.52, 114.85, 115.02, 115.42, 115.59, 126.72, 127.43, 127.49, 127.55, 127.62, 127.73, 128.52, 128.79, 129.10, 129.17, 133.91, 135.03, 140.33, 140.82, 160.69, 162.79, 171.31, 171.75.

[0336] Intermediate 23B: 3-[(4-Fluoro-benzyl)-(1-phenyl-ethyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0337] Intermediate 23B was prepared from Intermediate 23A using Method IX. HRMS (M+H) calcd for C₂₀H₂₁NO₄F: 358.1454; found: 358.1456. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.46(d, J=7), 1.55(d, J=7), 3.82(s), 3.89(s), 4.12(d, J=16), 4.24(d, J=18), 4.45(d, J=18), 4.77(d, J=16), 5.33(q, J=7), 6.08(s), 6.15(q, J=7), 6.90-7.36 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 17.00, 18.65, 45.74, 46.45, 51.73, 52.90, 52.98, 55.85, 93.75, 94.71, 115.12, 115.30, 115.57, 115.75, 127.02, 127.59, 127.65, 127.71, 127.93, 128.14, 128.68, 128.87, 129.00, 129.07, 132.97, 133.00, 133.78, 139.16, 139.71, 159.90, 160.11, 161.04, 162.99, 163.15, 163.32, 171.55, 171.86.

[0338] Compound 23: 3-[(4-Fluoro-benzyl)-(1-phenyl-ethyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0339] Compound 23 was prepared from Intermediate 23B using Method XI. HRMS (M−H) calcd for C₁₉H₁₇NO₄F: 342.1142; found: 342.1148. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.48(d, J=7), 1.54(d, J=7), 4.16(d, J=15), 4.25(d, J=18), 4.45(d, J=18), 4.76(d, J=15), 5.32(q, J=7), 6.13(s), 6.54(s), 6.85-7.36 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 16.98, 18.63, 45.82, 46.54, 52.05, 56.07, 93.81, 94.94, 115.20, 115.37, 115.67, 115.84, 127.02, 127.60, 127.68, 128.07, 128.27, 128.75, 128.94, 129.04, 129.11, 132.61, 132.64, 133.42, 138.84, 139.40, 159.05, 159.37, 161.07, 163.03, 164.83, 171.46, 171.76.

EXAMPLE 24

[0340] Intermediate 24A: N-(4-Chloro-benzyl)-N-(4-fluoro-benzyl)-acetamide

[0341] Intermediate 24A was prepared from 4-fluorobenzylamine and 4-chlorobenzylchloride using Method VI. HRMS (M+H) calcd for C₁₆H₁₆ClFNO: 292.0905; found: 292.0904. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.19(s), 2.21(s), 4.40(s), 4.53(s), 6.98-7.35 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.70, 47.31, 50.25, 115.43, 115.60, 115.92, 116.09, 127.78, 128.07, 128.13, 128.80, 129.22, 129.71, 130.02, 130.09, 131.81, 132.89, 133.36, 133.62, 134.78, 135.72, 161.29, 163.24, 171.02.

[0342] Intermediate 24B: 3-[(4-Chloro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0343] Intermediate 24B was prepared from Intermediate 24A using Method IX. HRMS (M+H) calcd for C₁₉H₁₈NO₄ClF: 378.0908; found: 378.0910. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.86(s), 3.87(s), 4.46(s), 4.57(s), 4.58(s), 6.29(s), 6.33(s), 7.00-7.35 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 47.42, 47.49, 49.41, 49.47, 53.01, 93.26, 115.68, 115.85, 116.02, 116.19, 128.09, 128.47, 128.54, 129.01, 129.31, 129.65, 130.04, 130.11, 130.99, 131.02, 131.87, 131.89, 133.80, 133.90, 134.04, 134.67, 160.36, 161.47, 161.54, 163.05, 163.43, 163.50, 171.41.

[0344] Compound 24: 3-[(4-Chloro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0345] Compound 24 was prepared from Intermediate 24B using Method X. HRMS (M−H) calcd for C₁₈H₁₄NO₄ClF: 362.0595; found: 362.0606. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 4.45(s), 4.56(s), 6.31(s), 6.35(s), 6.99-7.35 (overlapping m).

EXAMPLE 25

[0346] Intermediate 25A: N-(2,4-difluoro-benzyl)-N-(4-fluoro-benzyl)-acetamide

[0347] Intermediate 25A was prepared from 4-fluorobenzyl amine and 2,4-difluorobenzylbromide using Method VI. HRMS (M+H) calcd for C₁₆H₁₅F₃NO: 294.1106; found: 294.1105. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.14(s), 2.17(s), 4.39(s), 4.42(s), 4.46(s), 4.51(s), 6.69-7.30 (overlapping m).

[0348] Intermediate 25B: 3-[(2,4-Difluoro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0349] Intermediate 25B was prepared from Intermediate 25A using Method IX. HRMS (M+H) calcd for C₁₉H₁₇NO₄F₃: 380.1110; found: 380.1100. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.87(s), 3.88(s), 4.51(s), 4.52(s), 4.59(s), 4.62(s), 6.33(s), 6.77-7.40 (overlapping m).

[0350] Compound 25: 3-[(2,4-Difluoro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0351] Compound 25 was prepared from Intermediate 25B using Method X. HRMS (M−H) calcd for C₁₈H₁₃NO₄F₃: 364.0800; found: 364.0800. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 4.47(s), 4.48(s), 4.55(s), 4.58(s), 6.32(s), 6.73-7.34 (overlapping m).

EXAMPLE 26

[0352] Intermediate 26A: N-(3,5-difluoro-benzyl)-N-(4-fluoro-benzyl)-acetamide

[0353] Intermediate 26A was prepared from 4-fluorobenzylamine and 3,4-difluorobenzylamine using Method VI. HRMS (M+H) calcd for C₁₆H₁₄F₃NO: 294.1106; found: 294.1103. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.11(s), 2.13(s), 4.32(s), 4.35(s), 4.40(s), 4.44(s), 678-7.21 (overlapping m).

[0354] Intermediate 26B: 3-[(3,4-Difluoro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0355] Intermediate 26B was prepared from Intermediate 25A using Method IX. HRMS (M+H) calcd for C₁₉H₁₇NO₄F₃: 380.1110; found: 38.01116. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.88(s), 4.45(s), 4.48(s), 4.55(s), 4.59(s), 6.26(s), 6.34(s), 6.89-7.26 (overlapping m). ¹³C NMR(125 MHz, CDCl₃) δ: 47.24, 47.54, 49.07, 49.60, 53.08, 93.06, 93.16, 115.75, 115.87, 115.91, 116.08, 116.26, 117.22, 117.36, 117.52, 117.66, 117.99, 118.13, 122.61, 124.30, 124.33, 128.46, 128.52, 130.05, 130.12, 130.85, 131.72, 132.44, 133.22, 160.45, 160.50, 161.51, 161.57, 163.02, 163.47, 163.54, 171.39, 171.43.

[0356] Compound 26: 3-[(3,4-Difluoro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0357] Compound 26 was prepared from Intermediate 26B using Method X. HRMS (M−H) calcd for C₁₈H₁₃NO₄F₃: 364.0800; found 364.0792. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 4.43(s), 4.46(s), 4.53(s), 4.61(s), 6.27(s), 6.35(s), 6.86-7.26 (overlapping m).

EXAMPLE 27

[0358] Intermediate 27A: N-tert-Butyl-N-(4-fluoro-benzyl)-acetamide

[0359] Intermediate 27A was prepared from tert-butylamine and 4-fluorobenzyl bromide using Method VI. HRMS (M+H) calcd for C₁₃H₁₉FNO: 224.1451; found: 224.1456. ¹H NMR (500 MHz, CDCl₃) δ: 1.41 (s, 9), 2.08 (s, 3), 4.55 (s, 2), 7.04 (m, 2), 7.17 (m, 2). ¹³C NMR (125 MHz, CDCl₃) δ: 25.06, 28.78, 49.17, 57.71, 115.61, 115.78, 127.04, 127.10, 134.97, 134.99,160.97, 162.82, 172.16.

[0360] Intermediate 27B: 3-[tert-Butyl-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0361] Intermediate 27B was prepared from Intermediate 27A using Method IX. HRMS (M+H) calcd for C₁₆H₂₁NO₄F: 310.1455; found 310.1454. Anal. calcd for C₁₆H₂₀NO₄F: C, 62.12; H, 6.51; N, 4.52; found: C, 62.31; H, 6.71; N, 4.52. ¹H NMR (500 MHz, CDCl₃) δ: 1.47(s, 9), 3.2(s, 3), 4.62(s, 2), 6.20(s, 1), 7.06(dd, 2, J=9, 9), 7.16(dd, 2, J=5, 9). ¹³C NMR (125 MHz, CDCl₃) δ: 28.74, 48.27, 52.86, 58.85, 96.31, 115.81, 115.99, 116.61, 127.32, 127.38, 134.00, 159.61, 161.07, 163.02, 163.46, 173.36.

[0362] Compound 27: 3-[tert-Butyl-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0363] Compound 27 was prepared from Intermediate 27B using Method XI. HRMS (M−H) calcd for C₁₅H₁₇NO₄F: 294.1142; found: 294.1144. ¹H NMR (500 MHz, CDCl₃) δ: 1.47(s, 9), 4.62(s, 2), 6.12(br s, 1), 7.04(m, 2), 7.14(m, 2). ¹³C NMR (125 MHz, CDCl₃) δ: 28.68, 48.34, 59.15, 96.45, 115.86, 116.03, 127.28, 127.35, 133.64, 159.01, 161.09, 163.05, 165.61, 173.28.

EXAMPLE 28

[0364] Intermediate 28A: N-(3-Chloro-benzyl)-N-4-fluoro-benzyl)-acetamide

[0365] Intermediate 28A was prepared from 4-fluorobenzylamine and 3-chlorobenzylchloride using Method VI. HRMS (M+H) calcd for C₁₆H₁₆ClFNO: 292.0905; found: 292.0902. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.19(s), 2.23(s), 4.41(s), 4.55(s), 6.97-7.38 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.67, 47.50, 50.37, 115.44, 115.61, 115.92, 116.09, 124.47, 126.41, 126.52, 127.72, 128.00, 128.07, 128.14, 128.22, 129.92, 130.04, 130.11, 130.34, 131.77, 131.80, 132.88, 132.90, 134.56, 135.13, 138.49, 139.29, 161.31, 163.26, 171.05.

[0366] Intermediate 28B: 3-[(3-Chloro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0367] Intermediate 28B was prepared from Intermediate 28A using Method IX. HRMS (M+H) calcd for C₁₉H₁₈NO₄FCl: 378.0908; found: 378.0903. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.87(s), 3.88(s), 4.47(s), 4.48(s), 4.59 (s), 4.60(s), 6.28(s), 6.35(s), 7.01-7.31 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 47.57, 47.59, 49.49, 49.60, 53.05, 93.23, 93.24, 115.70, 115.87, 116.04, 116.21, 124.78, 126.33, 126.82, 128.12, 128.20, 128.38, 128.49, 128.55, 130.07, 130.14, 130.44, 130.94, 130.96, 131.83, 131.85, 134.77, 135.16, 137.52, 138.22, 160.38, 160.39, 161.49, 161.55, 163.05, 163.08, 163.45, 163.51, 171.44.

[0368] Compound 28; 3-[(3-Chloro-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0369] Compound 28 was prepared from Intermediate 28B using Method X. HRMS (M+H) calcd for C₁₈H₁₆NO₄ClF: 364.0752; found: 364.0758. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 4.48(s), 4.49(s), 4.60(s), 4.61(s), 6.35(s), 6.42(s), 7.02-7.34 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 47.49, 49.57, 49.70, 93.57, 115.76, 115.94, 116.11, 116.28, 124.77, 126.35, 126.80, 128.23, 128.49, 128.57, 130.11, 130.18, 130.49, 134.81, 135.21, 137.23, 137.94, 159.45, 164.76, 171.34.

EXAMPLE 29

[0370] Intermediate 29A: N-(4-Fluoro-benzyl)-N-isopropyl-acetamide

[0371] Intermediate 29A was prepared from 4-fluorobenzylbromide and isopropylamine using Method VI. HRMS (M+H) calcd for C₁₂H₁₇FNO: 210.1294; found: 210.1293. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.08 (d, J=7), 1.13(d, J=7), 2.00(s), 2.23(s), 4.12(p, J=7), 4.42(s), 4.49(s), 4.86(p, J=7), 6.93(m), 7.05(m), 7.19(m). ¹³C NMR (125 MHz, CDCl₃) δ: 20.33, 21.51, 22.03, 22.59, 43.05, 45.51, 46.31, 49.79, 114.99, 115.16, 115.57, 115.74, 127.33, 128.64, 134.17, 135.42, 160.71, 160.93, 162.65, 162.89, 170.70, 171.36.

[0372] Intermediate 29B: 3-[(4-Fluoro-benzyl)-isopropyl-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0373] Intermediate 29B was prepared from Intermediate 29A using Method IX. HRMS (M+H) calcd for C₁₅H₁₉NO₄F: 296.1298; found: 296.1299. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.14(d, J=7), 1.19(d, J=7), 3.81(s), 3.90(s), 4.28(heptet, J=7), 4.49(s), 4.59(s), 4.84(heptet, J=7), 6.03(s), 6.40(s), 6.97-7.22 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 20.23, 21.51, 43.51, 45.55, 46.04, 49.13, 52.88, 52.99, 93.54, 94.71, 115.32, 115.49, 115.75, 115.92, 127.57, 127.64, 128.50, 128.57, 133.14, 134.11, 159.74, 159.95, 160.90, 161.13, 162.85, 163.09, 163.25, 163.46, 171.08, 171.65.

[0374] Compound 29: 3-[(4-Fluoro-benzyl)-isopropyl-carbamoyl]-2-hydroxy-acrylic Acid

[0375] Compound 29 was prepared from Intermediate 29B using Method XI. HRMS (M−H) calcd C₁₄H₁₅NO₄F: 280.9851; found: 280.988. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.16(d, J=7), 1.20(d, J=7), 4.28(heptet, J=7), 4.51(s), 4.61(s), 4.82(heptet, J=7), 6.10(s), 6.47(s), 7.03(m), 7.15(m), 7.21(m).

EXAMPLE 30

[0376] Intermediate 30A: N-Methyl-N-(4-methyl-benzyl)-acetamide

[0377] Intermediate 30A was prepared from N-(4-methyl-benzyl)-acetamide and methyl iodide using Method VII. HRMS (M+H) calcd for C₁₁H₁₆NO: 178.1232; found: 178.1230. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.14 (s), 2.15 (s), 2.33 (s), 2.35 (s), 2.90 (s), 2.92 (s), 4.48 (s), 4.54 (s), 7.05-7.18 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.07, 21.12, 21.46, 21.68, 33.68, 35.44, 50.33, 54.05, 126.32, 128.10, 129.27, 129.63, 133.44, 134.30, 137.04, 137.41, 170.74, 171.08.

[0378] Intermediate 30B: 2-Hydroxy-3-[methyl-(4-methyl-benzyl)-carbamoyl]-acrylic Acid Methyl Ester

[0379] Intermediate 30B was prepared from Intermediate 30A using Method IX. HRMS (M+H) calcd for C₁₄H₁₈NO₄: 264.1236; found: 264.1243. Anal calcd for C₁₄H₁₇NO₄: C, 63.96; H, 6.50; N, 5.32; found: C, 63.57; H, 6.50; N, 5.28. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) 6:2.34 (s), 2.99 (s), 3.86 (s), 3.89 (s), 4.54 (s), 4.61 (s), 6.29 (s), 6.34 (s), 7.06-7.18 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.12, 33.47, 34.75, 50.37, 52.91, 53.09, 93.56, 93.66, 126.65, 128.00, 129.48, 129.71, 132.51, 133.16, 137.53, 137.86, 159.59, 163.35, 170.87, 171.19.

[0380] Compound 30: 2-Hydroxy-3-[methyl-(4-methyl-benzyl)-carbamoyl]-acrylic Acid

[0381] Compound 30 was prepared from Intermediate 30B using Method XI. HRMS (M−H) calcd for C₁₃H₁₄NO₄: 248.0923; found: 248.0926. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.34 (s), 3.01 (s), 3.02 (s), 4.55 (s), 4.62 (s), 6.36 (s), 6.42 (s), 7.06-7.18 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.13, 33.72, 34.85, 50.58, 53.23, 93.67, 93.74, 126.69, 128.03, 129.54, 129.77, 132.20, 132.83, 137.68, 138.00, 158.90, 159.111, 165.36, 170.80, 171.08.

EXAMPLE 31

[0382] Intermediate 31A: N-(4-Methoxy-benzyl)-N-methyl-acetamide

[0383] 4-Methoxybenzyl amine (3.8 grams, 27.8 mmol) was dissolved in 100 mL of methylene chloride, to this was added 100 mL of satd NaHCO₃ (aq.) followed by acetyl chloride (3.0 mL, 41.7 mmol). After stirring 1 h, an additional 41.7 mmol of acetyl chloride was added and the resulting mixture stirred overnight. The organic layer was separated, washed with satd NaCl (aq.), dried over Na₂SO₄, filtered and solvent removed under vacuum. Crude N-(4-methoxybenzyl)-acetamide was purified by flash column chromatography (SiO₂, 2% EtOH in methylene chloride) 1.75 grams (35% yield) as a white solid.

[0384] Sodium hydride (60% in mineral oil) (1.11 grams, 27.4 mmol) was measured into a round bottom flask and triturated with hexanes. To this was added pure N-(4-methoxybenzyl)-acetamide (1.23 grams, 6.9 mmol) followed by iodomethane (1.95 grams, 13.7 mmol)and the resulting mixture stirred overnight. The reaction was filtered and the solvent removed under vacuum. The crude product was purified by flash column chromatography (SiO₂, 2% EtOH in methylene chloride) to yield 1.2 grams of a colorless oil. HRMS (M+H) calcd for C₁₁H₁₆NO₂: 194.1181; found: 194.1177. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.13 (s), 2.15 (s), 2.89 (s), 2.90 (s), 3.78 (s), 3.80 (s), 4.45 (s), 4.50 (s), 6.86 (m), 7.08 (d, J=9), 7.17 (d, J=9). ¹³C NMR (125 MHz, CDCl₃) δ: 21.50, 21.91, 33.49, 35.33, 49.95, 53.72, 55.28, 113.95, 114.32, 127.66, 128.46, 129.44, 129.52, 158.95, 159.13, 170.63, 170.91.

[0385] Intermediate 31B: 2-Hydroxy-3-[(4-methoxy-benzyl)-methyl-carbamoyl]-acrylic Acid Methyl Ester

[0386] Intermediate 31B was prepared from Intermediate 31A using Method IX. HRMS (M+H) calcd for C₁₄H₁₈NO₅: 280.1185; found: 280.1188. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.98 (s), 3.80 (s), 3.89 (s), 3.90 (s), 4.52 (s), 4.58 (s), 6.28 (s), 6.36 (s), 6.88 (m), 7.10 (d, J=8), 7.18 (d, J=8). ¹³C NMR (125 MHz, CDCl₃) δ: 33.30, 34.62, 50.03, 52.77, 52.91, 55.32, 93.53, 93.69, 114.18, 114.42, 127.49, 128.05, 128.28, 129.44, 159.27, 159.42, 159.57, 163.35, 170.80, 171.08.

[0387] Compound 31: 2-Hydroxy-3-[(4-methoxy-benzyl)-methyl-carbamoyl]-acrylic Acid

[0388] Compound 31 was prepared from Intermediate 31B using Method XI. HRMS (M−H) calcd for C₁₃H₁₄NO₅: 264.0872; found: 264.0874. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.99 (s), 3.00 (s), 3.80 (s), 4.52 (s) 4.59 (s), 6.34 (s), 6.43 (s), 6.89 (m), 7.10 (d, J=8), 7.19 (d, J=8). ¹³C NMR (125 MHz, CDCl₃) δ: 33.52, 34.71, 50.25, 52.90, 55.35, 93.45, 114.25, 114.38, 114.49, 127.19, 127.95, 128.12, 129.48, 129.70, 159.03, 159.21, 159.32, 159.48, 164.89, 170.77, 171.01.

EXAMPLE 32

[0389] Intermediate 32A: N-Ethyl-N-(4-fluoro-benzyl)-acetamide

[0390] Intermediate 32A was prepared from 4-fluorobenzylbromide and N-ethylacetamide using Method VII. HRMS (M+H) calcd C₁₁H₁₅FNO: 196.1138; found: 196.1137. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.11 (m), 2.10 (s), 2.17 (s), 3.25 (q, J=7), 3.40 (q, J=7), 4.48 (s), 4.54 (s), 6.97-7.26 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 12.67, 13.61, 21.29, 21.79, 40.70, 42.46, 47.12, 50.89, 115.28, 115.44, 115.74, 115.91, 127.87, 127.94, 129.65, 129.71, 132.64, 132.67, 133.66, 133.69, 161.15, 163.10, 170.43, 170.61.

[0391] Intermediate 32B: 3-[Ethyl-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0392] Intermediate 32B was prepared from Intermediate 32A using Method IX. HRMS (M+H) calcd for C₁₄H₁₇NO₄F: 282.1142; found 282.1134. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.18 (overlapping m), 3.35 (q, J=7), 3.46 (q, J=7), 3.85 (s), 3.89 (s), 4.54 (s), 4.60 (s), 6.22 (s), 6.26 (s), 6.99-7.25 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 12.62, 14.00, 41.06, 42.16, 47.70, 50.10, 52.92, 52.96, 93.55, 93.59, 115.55, 115.72, 115.88, 116.05, 128.24, 128.31, 129.67, 129.73, 132.63, 159.80, 161.35, 163.31, 163.34, 170.60, 170.98.

[0393] Compound 32: 3-[Ethyl-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0394] Compound 32 was prepared from Intermediate 32B using Method XI. HRMS (M−H) calcd for C₁₃H₁₃NO₄: 266.0829; found: 266.0829,1 ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.19 (overlapping m), 3.36 (q, J=7), 3.47 (q, J=7), 4.55 (s), 4.61 (s), 6.30 (s), 6.33 (s), 7.03 (m), 7.16 (m), 7.25 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 12.58, 13.96, 41.32, 42.31, 47.91, 50.22, 93.46, 115.63, 115.80, 115.96, 116.13, 128.29, 128.35, 129.71, 129.78, 131.45, 132.28, 132.31, 159.331, 159.39, 163.37, 164.90, 170.58, 170.97.

EXAMPLE 33

[0395] Intermediate 33A: N-(3-Methoxy-benzyl)-N-methyl-acetamide

[0396] Intermediate 33A was prepared from N-methylacetamide and 3-methoxybenzylbromide using Method VII. HRMS (M+H) calcd for C₁₁H₁₆NO₂: 194.1181; found: 194.1180. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.13 (s), 2.14 (s), 2.91 (s), 2.93 (s), 3.78 (s), 3.79 (s), 4.48 (s), 4.55 (s), 6.69-6.83 (overlapping m), 7.21-7.29 (overlapping m).

[0397] Intermediate 33B: 2-Hydroxy-3-[(3-methoxy-benzyl)-methyl-carbamoyl]-acrylic Acid Methyl Ester

[0398] Intermediate 33B was prepared from Intermediate 33A using Method IX. HRMS (M+H) calcd for C₁₄H₁₈NO₅: 280.1185; found 280.1183. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.01 (s), 3.79 (s), 3.85 (s), 3.89 (s), 4.55 (s), 4.62 (s), 6.30 (s), 6.31 (s), 6.70-6.85 (overlapping m), 7.29 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.62, 34.89, 50.58, 52.93, 53.22, 55.27, 93.46, 93.59, 112.57, 113.02, 113.67, 118.81, 120.19, 129.84, 130.17, 137.24, 137.81, 159.65, 160.01, 160.19, 163.32, 170.95, 171.28.

[0399] Compound 33: 2-Hydroxy-3-[(3-methoxy-benzyl)-methyl-carbamoyl]-acrylic Acid

[0400] Compound 33 was prepared from Intermediate 33B using Method XI. HRMS (M−H) calcd for C₁₃H₁₄NO₅: 264.0872; found: 264.0868. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.02 (s), 3.03 (s), 3.80 (s), 4.56 (s), 4.63 (s) 6.36 (s), 6.38 (s), 6.70-6.85 (overlapping m), 7.26 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.82, 34.98, 50.75, 53.33, 55.30, 93.55, 112.62, 113.08, 113.14, 113.36, 113.73, 114.76, 118.86, 120.22, 122.03, 129.90, 130.28, 136.97, 137.54, 159.21, 159.39, 159.99, 160.06, 165.18, 170.96, 171.25.

EXAMPLE 34

[0401] Intermediate 34A: N-Biphenyl-3-ylmethyl-N-methyl-acetamide

[0402] C-Biphenyl-3-yl-methylamine (700 mg, 3.8 mmol) was dissolved in 38 mL of CH₂Cl₂. To this was added 38 mL of satd NaHCO₃ (aq) followed by acetyl chloride (1.41 mL 19,8 mmol). The resulting mixture was stirred 45 min. The organic layer was separated, washed with satd NaCl, dried over Na₂SO₄, filtered and solvent removed under vacuum to yield 1.1 grams of N-biphenyl-3-ylmethyl-acetamide.

[0403] N-biphenyl-3-ylmethyl-acetamide (860 mg, 3.8 mmol) was dissolved in 10 mL of toluene. To this was added 611 mg of 60% NaH (mineral oil) and MeI (0.48 mL, 7.6 mmol). The resulting mixture was stirred overnight then filtered. The solvent was removed under vacuum to yield 980 mg (108% yield) of N-biphenyl-3-ylmethyl-N-methyl-acetamide. HRMS ((M+H) calcd for C₁₆H₁₈N): 240.1389; found: 240.1398. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.17 (s), 2.19 (s), 2.96 (s), 2.99 (s), 4.60 (s), 4.66 (s), 7.15-7.60 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.55, 21.91, 33.84, 35.61, 50.66, 54.33, 125.05, 125.16, 126.25, 126.55, 126.85, 127.00, 127.20, 127.23, 127.42, 127.65, 128.79, 128.90, 129.06, 129.45, 137.19, 137.95, 140.65, 140.95, 141.64, 142.12, 170.79, 171.08.

[0404] Intermediate 34B: 3-(Biphenyl-3-ylmethyl-methyl-carbamoyl)-2-hydroxy-acrylic Acid Methyl Ester

[0405] Intermediate 34B was prepared from Intermediate 34A using Method IX. HRMS (M+H) calcd for C₁₉H₂₀NO₄: 326.1392; found: 326.1398. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.04 (s), 3.06 (s), 3.87 (s), 3.90 (s), 4.65 (s), 4.73 (s), 6.33 (s), 6.38 (s), 7.16-7.59 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.68, 34.95, 50.69, 52.95, 53.34, 93.48, 93.65, 125.40, 125.44, 126.66, 126.76, 126.87, 126.93, 127.20, 127.57, 127.72, 128.88, 128.94, 129.31, 129.58, 136.22, 136.82, 140.53, 140.73, 141.88, 142.17, 159.69, 163.32, 171.01, 171.33.

[0406] Compound 34: 3-(Biphenyl-3-ylmethyl-methyl-carbamoyl)-2-hydroxy-acrylic Acid

[0407] Compound 34 was prepared from Intermediate 34B using Method X. HRMS (M+H) calcd for C₁₈H₁₈NO₄: 312.1236; found: 312.1250. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.05 (s), 3.08 (s), 4.65 (s), 4.73 (s), 6.39 (s), 6.46 (s), 7.15-7.59 (overlapping m).

EXAMPLE 35

[0408] Intermediate 35A: N-(2,4-Dimethoxy-benzyl)-N-(4-fluoro-benzyl)-acetamide

[0409] Intermediate 35A was prepared from (2,4-dimethoxy-benzyl)-(4-fluoro-benzyl)-amine using Method IV. HRMS (M+H) calcd for C₁₈H₂₁FNO₃: 318.1506; found: 318.1505. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.14 (s), 2.22 (s), 3.71 (s), 3.77 (s), 3.79 (s), 3.81 (s), 4.34 (s), 4.46 (s), 4.51 (s), 4.55 (s), 6.45 (m), 6.92-7.22 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.61, 21.82, 42.89, 46.56, 47.10, 50.86, 55.19, 55.46, 98.30, 98.68, 103.87, 104.25, 115.16, 115.33, 115.56, 115.73, 116.50, 117.85, 127.83, 127.90, 128.29, 129.79, 129.85, 131.00, 132.97, 133.53, 133.55, 158.35, 158.58, 160.34, 160.66, 161.09, 163.03, 171.11, 171.46.

[0410] Intermediate 35B: 3-[(2,4-Dimethoxy-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0411] Intermediate 35B was prepared from Intermediate 35A using Method IX. HRMS (M+H) calcd for C₂₁H₂₃NO₆F: 404.1510; found: 404.1514. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.73 (s), 3.78 (s), 3.80 (s), 3.81 (s), 3.85 (s), 3.87 (s), 4.42 (s), 4.53 (s), 4.58 (s), 4.60 (s), 6.27 (s), 6.42 (s), 6.45 (s), 6.94-7.23 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 43.10, 45.55, 47.29, 49.88, 52.91, 55.20, 55.26, 55.46, 93.77, 94.39, 98.43, 98.68, 104.09, 104.36, 115.44, 115.61, 115.67, 115.76, 115.84, 116.66, 128.26, 128.32, 128.86, 129.80, 129.86, 131.02, 132.05, 132.50, 132.52, 158.37, 158.60, 159.40, 159.83, 160.70, 160.94, 161.28, 163.24, 163.31, 163.41, 171.36, 171.46.

[0412] Compound 35: 3-[(2,4-Dimethoxy-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0413] Compound 35 was prepared from Intermediate 35B using Method XI. HRMS (M+H) calcd for C₂₀H₂₁NO₆F: 390.1353; found: 390.1362.

EXAMPLE 36

[0414] Intermediate 36A: N-(4-Benzyloxy-benzyl)-N-methyl-acetamide

[0415] Intermediate 36A was prepared from 4-benzyloxy-benzylchloride using Method VI. HRMS (M+H) calcd for C₁₇H₂₀NO₂: 270.1494; found: 270.1491. ¹H NMR and ¹3C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.14 (s), 2.16 (s), 2.90 (s), 2.92 (s), 4.46 (sO, 4.52 (s), 5.05 (s), 5.07 (s), 6.92-7.44 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.52, 21.93, 33.52, 35.37, 49.98, 53.73, 70.06, 70.13, 114.92, 115.29, 127.49, 127.53, 127.62, 127.68, 127.99, 128.07, 128.61, 128.65, 128.67, 128.80, 129.46, 129.85, 136.84, 137.00, 158.19, 158.35, 170.62, 170.89.

[0416] Compound 36: 3-[(4-Benzyloxy-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0417] Compound 36 was prepared from Intermediate 36A using Method XII. HRMS (M+H) calcd for C₁₉H₂₀NO₅: 342.1342; found: 342.1352. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) 2.90 (s), 4.43 (s), 4.50 (s) 4.97 (s), 6.21 (s), 6.29 (s), 6.87-7.35 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.42, 34.62, 49.91, 52.66, 69.99, 93.20, 93.34, 115.03, 115.25, 127.45, 127.89, 127.98, 128.08, 128.57, 128.66, 129.34, 136.73, 136.82, 158.32, 158.47, 160.24, 164.44, 170.99, 171.24.

EXAMPLE 37

[0418] Intermediate 37A: N-Methyl-N-(3-trifluoromethyl-benzyl)-acetamide

[0419] Intermediate 37A was prepared from 3-trifluorobenzyl bromide using Method VII. HRMS (M+H) calcd for C₁₁H₁₃F₃NO: 232.0949; found: 232.0945. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.14 (s), 2.17 (s), 2.94 (s), 4.58 (s), 4.62 (s), 7.37-7.55 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.44, 21.77, 33.76, 35.71, 122.97. 123.12, 123.15, 124.23, 124.26, 124.29, 124.56, 124.59, 124.62, 124.64, 125.13, 129.15, 129.53, 129.58, 130.55, 130.81, 131.07, 131.34, 131.59., 137.78, 138.48, 170.91, 170.95.

[0420] Intermediate 37B: 2-Hydroxy-3-[methyl-(3-trifluoromethyl-benzyl)-carbamoyl]-acrylic Acid Methyl Ester

[0421] Intermediate 37B was prepared from Intermediate 37A using Method IX. HRMS (M+H) calcd for C₁₄H₁₅NO₄F₃: 318.0953; found: 318.0948. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.02 (s), 3.03 (s), 3.84 (s), 3.88 (s), 4.64 (s), 4.70 (s), 6.27 (s), 6.31 (s), 7.36-7.59 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.65, 35.05, 50.34, 52.87, 52.97, 93.04, 93.42, 122.86, 123.46, 123.49, 124.55, 124.58, 124.61, 124.64, 124.68, 124.71, 125.02, 129.41, 129.74, 129.81, 130.78, 131.03, 131.25, 131.36, 131.55, 131.62, 136.79, 137.39, 159.82, 159.93, 163.12, 163.17, 171.14, 171.35.

[0422] Compound 37: 2-Hydroxy-3-[methyl-(3-trifluoromethyl-benzyl)-carbamoyl]-acrylic Acid

[0423] Compound 37 was prepared from Intermediate 37B using Method X. Anal Calcd for C₁₃H₁₂NO₄F₃: C, 51.49; H, 3.98; N, 4.62; found: C, 51.72; H, 3.76; N, 4.39. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.05 (s), 4.66 (s), 4.72 (s), 6.36 (s), 6.39 (s), 7.36-7.61 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.85, 35.14, 50.53, 52.98, 93.32, 93.72, 122.83, 123.51, 124.65, 124.68, 124.82, 124.85, 124.99, 125.14, 129.48, 129.81, 131.13, 131.27, 131.39, 136.44, 137.07, 159.04, 159.17, 165.05, 165.13, 171.04, 171.26.

EXAMPLE 38

[0424] Intermediate 38A: N-(2-Fluoro-benzyl)-N-methyl-acetamide

[0425] Intermediate 38A was prepared from 2-fluoro-benzyl bromide using Method VII. HRMS (M+H) calcd for C₁₀H₁₃FNO: 182.0981; found: 182.0982. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.14 (s), 2.16 (s), 2.94 (s), 2.97 (s), 4.56 (s), 4.64 (s), 7.01-7.31 (overlapping m).

[0426] Intermediate 38B: 3-[(2-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0427] Intermediate 38B was prepared from Intermediate 38A using Method IX. HRMS (M+H) calcd for C₁₃H₁₅NO₄F: 268.0985; found: 268.0992. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.02 (s), 3.05 (s), 3.84 (s), 3.87 (s), 4.62 (s), 4.70 (s), 6.28 (s), 6.32 (s), 7.03-7.30 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.55, 35.21, 44.27, 44.30, 47.24, 47.28, 93.40, 93.57, 115.40, 115.57, 115.70, 115.87, 122.66, 122.77, 123.15, 123.27, 124.53, 124.55, 124.65, 124.68, 128.26, 128.29, 129.53, 129.60, 129.84, 129.91, 130.34, 130.37, 159.59, 159.65, 160.07, 161.61, 162.03, 163.24, 171.11, 171.34.

[0428] Compound 38: 3-[(2-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid:

[0429] Compound 38 was prepared from Intermediate 38B using Method XI. HRMS (M+H) calcd for C₁₂H₁₃NO₄F: 254.0829; found: 254.0833. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.04 (s), 3.07 (s), 4.64 (s), 4.72 (s), 6.36 (s), 6.41 (s), 7.05-7.20 (overlapping m), 7.31 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.75, 35.29, 44.84, 44.51, 47.43, 47.46, 93.81, 93.85, 115.46, 115.64, 115.78, 115.95, 122.39, 122.51, 122.90, 123.02, 124.58, 124.60, 124.71, 124.73, 128.40, 128.43, 129.67, 129.74, 130.00, 130.06, 130.40, 130.43, 158.92, 159.03, 159.68, 160.08, 161.64, 162.04, 165.48, 171.03, 171.23

[0430] EXAMPLE 39

[0431] Intermediate 39A: N-Biphenyl-2-ylmethyl-N-methyl-acetamide

[0432] Intermediate 39A was prepared from C-Biphenyl-2-yl-methylamine using the same Method as Intermediate 34A. LCMS (M+H) calcd for C₁₆H₁₈NO: 240.1; found: 240.1

[0433] Intermediate 39B: 3-(Biphenyl-2-ylmethyl-methyl-carbamoyl)-2-hydroxy-acrylic Acid Methyl Ester

[0434] Intermediate 39B was prepared from Intermediate 39A using Method IX. HRMS (M+H) calcd for C₁₉H₂₀NO₄: 326.1392; found: 326.1396. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.80 (s), 2.90 (s), 3.86 (s), 3.89 (s), 3.92 (s), 4.51 (s), 4.68 (s), 6.12 (s), 6.21 (s), 7.18-7.46 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.53, 34.76, 48.13, 51.34, 52.88, 52.94, 53.67, 93.48, 93.52, 126.43, 127.41, 127.47, 127.55, 127.62, 127.81, 127.96, 128.13, 128.39., 128.62, 128.92, 129.05, 130.30, 130.49, 132.90, 133.29, 140.09, 140.44, 141.70, 142.05, 159.32, 159.49, 163.28, 163.36, 170.96, 171.25.

[0435] Compound 39: 3-(Biphenyl-2-ylmethyl-methyl-carbamoyl)-2-hydroxy-acrylic Acid

[0436] Compound 39 was prepared from Intermediate 39B using Method XI. HRMS (M−H) calcd for C₁₈H₁₆NO₄: 310.1079; found: 310.1074. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.80 (s), 2.91 (s), 4.52 (s), 4.69 (s), 6.16 (s), 6.27 (s), 7.18-7.45 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.70, 34.82, 48.33, 51.50, 93.51, 93.79, 126.58, 127.45, 127.61, 127.66, 127.94, 128.01, 128.15, 128.43, 128.68, 128.90, 129.03, 130.36, 130.56, 132.63, 133.02, 140.01, 140.38, 141.80, 142.09, 158.63, 159.02, 165.27, 170.88, 171.11.

EXAMPLE 40

[0437] Intermediate 40A: N-(3-Fluoro-benzyl)-N-methyl-acetamide

[0438] Intermediate 40A was prepared from 3-fluorobenzoyl chloride using Methods II and IV. HRMS (M+H) calcd for C₁₀H₁₃FNO: 182.0981; found: 182.0982. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. 1H NMR (500 MHz, CDCl₃) δ: 2.07 (s), 2.10 (s), 2.87 (s), 2.88 (s), 4.45 (s), 4.51 (s), 6.80-7.28 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.68, 22.06, 34.08, 35.95, 50.49, 50.50, 54.08, 54.09, 113.47, 113.64, 114.45, 114.62, 114.81, 114.91, 114.98, 115.08, 122.08, 122.10, 123.76, 123.79, 130.34, 130.41, 130.85, 130.91, 139.60, 139.66, 140.26, 140.32, 162.33, 162.57, 164.29, 164.54, 171.08, 171.24.

[0439] Intermediate 40B: 3-[(3-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0440] Intermediate 40A was prepared from Intermediate 40A using Method IX. HRMS (M+H) calcd for C₁₃H₁₅NO₄F: 268.0985; found: 268.0987. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.03 (s), 3.86 (s), 3.90 (s), 4.58 (s), 4.65 (s), 6.27 (s), 6.31 (s), 6.99 (m), 7.31 (m). ¹³ C NMR (125 MHz, CDCl₃) δ: 33.68, 35.02, 50.26, 52.82, 52.99, 93.19, 93.46, 113.54, 113.72, 114.68, 114.85, 115.00, 115.17, 122.14, 123.44, 123.46, 130.36, 130.42, 130.72, 130.79, 138.80, 138.85, 159.78, 162.10, 163.24, 164.07, 171.05, 171.30.

[0441] Compound 40: 3-[(3-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0442] Compound 40 was prepared from Intermediate 40B using Method XI. HRMS (M−H) calcd for C₁₂H₁₁NO₄F: 252.0672.; found: 252.0668. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.04 (s), 4.59 (s), 4.65 (s), 6.35 (s), 6.38 (s), 6.87-7.03 (overlapping m), 7.33 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.90, 35.11, 50.43, 52.94, 93.61, 93.84, 113.55, 113.73, 114.73, 114.78, 114.90, 114.95, 115.10, 115.26, 122.19, 123.49, 130.42, 130.48, 130.80, 130.68, 137.99, 138.50, 138.56, 159.06, 162.09, 162.24, 164.06, 165.46, 170.94, 171.20.

EXAMPLE 41

[0443] Intermediate 41A: N-(4-Fluoro-naphthalen-1-ylmethyl)-N-methyl-acetamide

[0444] Intermediate 41A was prepared from 4-fluoro-naphthalene-1-carboxylic acid using Methods II and IV. HRMS (M+H) calcd for C₁₄H₁₅FNO: 232.1138; found: 232.1135. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.13 (s), 2.17 (s), 2.82 (s), 3.04 (s), 4.94 (s), 5.01 (s), 7.06-8.19 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.29, 22.07, 34.26, 34.80, 47.99, 51.78, 108.43, 108.59, 108.90, 109.06, 121.10, 121.15, 121.67, 121.71, 122.04, 122.06, 122.49, 122.56, 124.04, 124.13, 124.15, 126.32, 126.33, 126.44, 126.97, 127.03, 127.14, 127.17, 127.53, 127.57, 128.65, 128.68, 131.88, 132.96, 133.00, 157.52, 157.81, 159.53, 159.81, 170.55, 171.58.

[0445] Intermediate 41B: 3-[(4-Fluoro-naphthalen-1-ylmethyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0446] Intermediate 41B was prepared from Intermediate 41A using Method IX. HRMS (M+H) calcd for C₁₇H₁₇NO₄F: 318.1142; found: 318.1144. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.93 (s), 3.09 (s), 3.81 (s), 3.90 (s), 5.02 (s), 5.09 (s), 6.22 (s), 6.30 (s) 7.11 (m), 7.28 (m), 7.6 (m), 7.85 (d, J=8), 8.05 (m), 8.16 (m), 8.19 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.90, 34.09, 47.95, 50.85, 52.93, 52.99, 93.31, 93.76, 108.56, 108.72, 108.92, 109.08, 121.32, 121.36, 121.74, 121.78, 122.10, 123.33, 123.40, 123.60, 123.62, 124.11, 124.43, 126.51, 126.57, 126.99, 127.06, 127.37, 127.41, 127.76, 127.80, 132.80, 132.84, 158.02, 159.75, 159.88, 160.03, 163.19, 163.29, 170.73, 171.76.

[0447] Compound 41: 3-[(4-Fluoro-naphthalen-1-ylmethyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0448] Compound 41 was prepared from Intermediate 41B using Method XI. HRMS (M−H) calcd for C₁₆H₁₄NO₄F: 302.0829; found: 302.0821. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.00 (s), 3.04 (s), 5.08 (s), 5.20 (s), 6.17 (s), 6.31 (s), 7.11 (m), 7.33 (m), 7.40 (m), 7.69 (m), 8.12 (m).

EXAMPLE 42

[0449] Intermediate 42A: N-(4-Fluoro-benzyl)-N-(2-methoxy-ethyl)-acetamide

[0450] Intermediate 42A was prepared from 4-fluorobenzylamine and 1-bromo-2-methoxy ethane using Method VI. HRMS (M+H) calcd for C₁₂H₁₇FNO₂: 226.1243; found: 226.1244. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.17 (s), 2.24 (s), 3.30 (s), 3.31 (s), 3.43 (s), 3.55 (s), 4.63 (s), 4.64 (s), 6.98-7.23 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.25, 21.32, 46.08, 47.87, 48.46, 52.91, 58.85, 59.10, 70.25, 71.05, 115.40, 115.57, 115.82, 115.99, 127.92, 127.98, 129.73, 129.80, 132.09, 132.12, 132.96, 132.98, 158.91, 159.23, 161.26, 161.28, 163.22, 163.24, 172.34, 172.61.

[0451] Intermediate 42B: 3-[(4-Fluoro-benzyl)-(2-methoxy-ethyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0452] Intermediate 42B was prepared from Intermediate 42A using Method IX. HRMS (M+H) calcd for C₁₅H₁₉NO₅F: 312.1247; found: 312.1256. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) 6:3.32 (s), 3.58 (m), 3.85 (s), 3.89 (s), 4.67 (s), 4.69 (s), 6.25 (s), 6.31 (s), 7.03 (m), 7.15 (m), 7.24 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 45.84, 46.90, 48.87, 51.79, 52.97, 58.95, 59.16, 70.81, 70.89, 93.64, 93.89, 115.53, 115.70, 115.82, 115.99, 128.27, 128.33, 129.70, 129.77, 131.84, 131.86, 132.54, 132.56, 159.54, 159.83, 161.34, 161.38, 163.21, 163.29, 163.34, 171.17, 171.43.

[0453] Compound 42: 3-[(4-Fluoro-benzyl)-(2-methoxy-ethyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0454] Compound 42 was prepared from Intermediate 42B using Method XI. HRMS (M−H) calcd for C₁₄H₁₅NO₅F: 296.0934; found: 296.0940. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.22 (s), 3.45 (m), 3.57 (m), 4.64 (s), 4.73 (s), 6.17 (s), 6.32 (s), 7.15-7.33 (overlapping m).

EXAMPLE 43

[0455] Intermediate 43A: N-(4-Fluoro-benzyl)-N-(3-phenyl-propyl)-acetamide

[0456] 4-Fluorobenzylamine (11.4 g, 91 mmol) was dissolved in 910 mL of CH₂Cl₂. To this was added 910 mL of satd NaHCO₃ followed by acetyl chloride (23.4 mL, 329 mmol) stir 1 h. The organic layer was separated, washed with satd NaCl, dried over Na₂SO₄, filtered and solvent removed to yield 8.4 grams of N-(4-fluoro-benzyl)-acetamide.

[0457] N-(4-fluoro-benzyl)-acetamide (697 mg, 4.17 mmol) was suspended in toluene and treated with 668 mg of 60% NaH (mineral oil) followed by (3-bromopropyl)-benzene (1.27 mL, 8.34 mmol) and the resulting mixture stirred overnight. The mixture was filtered and the solvent removed. The crude product was purified by preparative HPLC (C₁₈, MeOH/H₂O-0.1% TFA) to yield 221 mg (19% yield) N-(4-Fluoro-benzyl)-N-(3-phenyl-propyl)-acetamide. HRMS (M+H) calcd for C₁₈H₂₁FNO: 286.1607; found: 286.1603. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.89 (m), 2.11 (s), 2.16 (s), 2.60 (t, J=7), 3.19 (dd, J=8, 8), 3.41 (dd, J=8, 8), 4.46 (s), 4.54 (s), 6.96-7.32 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 20.67, 21.21, 28.71, 29.53, 32.77, 33.14, 46.21, 47.25, 48.04, 51.60, 115.48, 115.65, 115.95, 116.12, 116.22, 126.04, 126.44, 128.01, 128.07, 128.28, 128.46, 128.68, 129.94, 130.01, 131.57, 131.59, 132.61, 132.64, 140.32, 141.19, 158.96, 159.28, 161.32, 161.37, 163.28, 163.34, 172.14, 172.46.

[0458] Intermediate 43B: 3-[(4-Fluoro-benzyl)-(3-phenyl-propyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0459] Intermediate 43B was prepared from Intermediate 43A using Method IX. HRMS (M+H) calcd for C₂₁H₂₃NO₄F: 372.1611; found: 372.1618. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) 6:1.92 (m), 2.62 (t, J=7), 3.26 (dd, J=8, 8), 3.44 (dd, J=8, 8), 3.86 (s), 3.89 (s), 4.50 (s), 4.57 (s), 6.17 (s), 6.24 (s), 6.97-7.33 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 28.91, 29.89, 32.75, 33.18, 45.90, 46.63, 48.08, 50.58, 52.99, 93.57, 115.56, 115.73, 115.90, 116.08, 126.11, 126.37, 128.27, 128.32, 128.39, 128.50, 128.68, 129.80, 129.87, 131.59, 131.62, 132.43, 132.46, 140.30, 141.07, 159.78, 159.86, 161.35, 161.44, 163.27, 163.31, 163.40, 170.78, 171.20.

[0460] Compound 43: 3-[(4-Fluoro-benzyl)-(3-phenyl-propyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0461] Compound 43 was prepared from Intermediate 43B using Method XI. HRMS (M−H) calcd for C₂₀H₁₉NO₄F: 356.1298; found: 356.1305. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.91 (m), 2.64 (m), 3.26 (dd, J=8, 8), 3.45 (dd, J=7, 7). 4.53 (s), 4.57 (s), 6.24 (s), 6.31 (s), 6.97-7.32 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ 28.84, 29.88, 32.71, 33.14, 46.08, 46.70, 48.26, 50.68, 93.54, 93.66, 115.62, 115.79, 115.98, 116.15, 126.16, 126.46, 128.24, 128.27, 128.36, 128.42, 128.52, 128.74, 128.83, 129.85, 129.92, 131.29, 132.15, 132.17, 140.15, 140.96, 159.14, 159.31, 161.41, 163.37, 165.03, 170.70, 171.16.

EXAMPLE 44

[0462] Intermediate 44A: N-Isopropyl-N-(3-phenyl)-acetamide

[0463] Intermediate 44A was prepared from (3-bromo-propyl)-benzene and isopropyl amine using Method VI. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.09 (d, J=7), 1.13 (d, J=7), 1.90 (m), 1.98 (s), 2.10 (s), 2.64 (t, J=7), 3.12 (m), 3.19 (m), 3.96 (heptet, J=7), 4.65 (heptet, J=7), 7.16-7.32 (overlapping m).

[0464] Intermediate 44B: 2-Hydroxy-3-[isopropyl-(3-phenyl-propyl)-carbamoyl]-acrylic Acid Methyl Ester

[0465] Intermediate 44A was prepared from Intermediate 44B using Method IX. HRMS (M+H) calcd for C₁₇H₂₄NO₄: 306.1705; found: 306.1699. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.13 (d, J=7), 1.18 (d, J=7), 1.94 (m), 2.67 (m), 3.18 (m), 3.29 (m), 3.88 (s), 4.14 (septet, J=7), 4.70 (septet, J=7), 6.06 (s), 6.29 (s), 7.14-7.33 overlapping m). ¹³CNMR (125 MHz, CDCl₃) 20.30, 21.27, 30.84, 32.34, 33.21, 33.61, 40.96, 42.39, 45.50, 48.58, 52.89, 93.60, 94.52, 126.02, 126.34, 126.61, 128.28, 128.34, 128.44, 128.52, 128.67, 128.74, 139.47, 140.40, 141.30, 142.04, 159.39, 159.58, 163.50, 163.65, 170.38, 170.46.

[0466] Compound 44: 2-Hydroxy-3-[isopropyl-(3-phenyl-propyl)-carbamoyl]-acrylic Acid

[0467] Compound 44 was prepared from Intermediate 44B using Method XI. HRMS (M+H) calcd for C₁₆H₂₂NO₄: 292.1549; found: 292.1550. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.14 (d, J=7), 1.19 (d, J=7), 1.96 (m), 2.67 (m), 3.18 (m), 3.30 (m), 4.14 (heptet, J=7), 4.70 (heptet, J=7), 6.11 (s), 6.35 (s), 7.16-7.34 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 20.28, 20.80, 21.20, 30.75, 32.28, 33.16, 33.57, 41.14, 42.47, 45.83, 48.79, 93.15, 94.40, 117.13, 126.08, 126.42, 128.27, 128.33, 128.47, 128.74, 140.24, 141.84, 159.15, 159.57, 165.66, 165.77, 170.41, 177.45.

EXAMPLE 45

[0468] Intermediate 45A: N-(4-Chloro-benzyl)-N-methyl-acetamide

[0469] Intermediate 45A was synthesized from 4-chlorobenzylamine using the same procedure as Intermediate 34A. HRMS (M+H) calcd for C₁₀H₁₃ClNO: 198.0686; found: 198.0686. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.13 (s), 2.14 (s), 2.90 (s), 2.91 (s) 4.84 (s), 4.53 (s), 7.09-7.34 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.46, 21.84, 33.70, 35.58, 50.04, 53.67, 127.69, 128.75, 129.16, 129.43, 133.18, 133.51, 135.09, 135.94, 170.78, 170.93.

[0470] Intermediate 45B: 3-[(4-Chloro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0471] Intermediate 45A was prepared from Intermediate 45A using Method IX. HRMS (M+H) calcd for C₁₃H₁₅NO₄Cl: 284.0690; found: 284.0696. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.01 (s) 3.87 (s), 3.90 (s), 4.56 (s), 4,62 (s), 6.29 (s), 7.12-7.31 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.57, 34.90, 50.08, 52.70, 53.00, 93.21, 93.49, 117.03, 117.12, 128.01, 129.00, 129.29, 129.37, 133.70, 134.08, 134.78, 159.75, 163.24, 170.99.

[0472] Compound 45: 3-[(4-Chloro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0473] Compound 45 was prepared from Intermediate 45B using Method XI. HRMS (M+H) calcd for C₁₂H₁₃NO₄Cl: 270.0533; found: 270.0536. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.02 (s), 4.56 (s), 4.63 (s), 6.36 (s), 7.11-7.36 (overlapping m).

EXAMPLE 46

[0474] Intermediate 46A: N-[3-(4-Fluoro-phenyl)-propyl]-N-methyl-acetamide

[0475] Intermediate 46A was prepared from 3-(4-fluoro-phenyl)-propionic acid using Method II and IV. HRMS (M+H) calcd for C₁₂H₁₆FNO: 210.1294; found: 210.1292. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.83 (m), 2.00 (s), 2.05 (s), 2.58 (m), 2.90 (s), 2.94 (s), 3.26 (dd, J=7, 7), 3.39 (dd, J=7, 7), 6.96 (m), 7.12 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.19, 21.96, 28.96, 29.87, 32.02, 32.36, 33.17, 36.09, 47.15, 50.08, 115.00, 115.17, 115.28, 115.45, 129.55, 129.59, 129.61, 129.65, 136.40, 137.28, 160.30, 160.46, 162.24, 162.40, 170.37, 170.54.

[0476] Intermediate 46B: 3-{[3-(4-Fluoro-phenyl)-propyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid Methyl Ester

[0477] Intermediate 46B was prepared from Intermediate 45A using Method IX. HRMS (M+H) calcd for C₁₅H₁₉NO₄F: 296.1298; found: 296.1302. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.89 (m), 2.60 (m), 2.98 (s), 3.02 (s), 3.33 (m), 3.45 (m), 3.86 (s), 6.09 (s), 6.20 (s), 6.96 (m), 7.12 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 28.85, 29.88, 31.83, 32.28, 33.54, 35.35, 47.30, 49.25, 52.88, 93.36, 93.64, 115.11, 115.27, 115.32, 115.49, 129.59, 129.65, 136.03, 136.05, 136.80, 136.82, 159.29, 159.39, 160.38, 160.50, 162.32, 162.44, 163.33, 163.36, 170.62, 170.74.

[0478] Compound 46: 3-{[3-(4-Fluoro-phenyl)-propyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0479] Compound 46 was prepared from Intermediate 46B using Method XI. HRMS (M+H) calcd for C₁₄H₁₇NO₄F: 282.1142; found: 282.1148. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.85-1.96 (overlapping m), 2.61 (m), 3.01 (s), 3.04 (s), 3.36 (dd, J=7, 7), 3.47 (dd, J=7, 7), 6.20 (s), 6.28 (s), 6.96 (m), 7.13 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 28.80, 29.89, 31.84, 32.26, 33.81, 35.49, 44.81, 47.55, 49.49, 93.54, 93.64, 115.15, 115.32, 115.38, 115.55, 129.58, 129.64, 135.95, 136.70, 142.04, 158.81, 159.02, 160.41, 160.54, 162.35, 162.48, 165.43, 170.54, 171.68.

EXAMPLE 47

[0480] Intermediate 47A: N-(4-Fluoro-benzyl)-N-(2-phenoxy-ethyl)-acetamide

[0481] Intermediate 47A was prepared from (2-chloro-ethoxy)-benzene and 4-fluorobenzyl amine using Method VI. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.13 (s), 2.29 (s), 3.64 (t, J=5), 3.73 (t, J=5), 4.02 (t, J=5), 4.17 (t, J=5), 4.67 (s), 4.69 (s), 6.82-7.30 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.77, 21.81, 45.73, 47.12, 48.00, 53.17, 65.35, 66.50, 114.34, 115.38, 115.56, 115.79, 115.96, 120.99, 121.42, 128.03, 128.09, 129.55, 129.63, 129.67, 129.74, 132.60, 132.62, 133.38, 133.41, 158.14, 158.46, 161.20, 161.26, 163.15, 163.21, 171.26, 171.32.

[0482] Intermediate 47B: 3-[(4-Fluoro-benzyl)-(2-phenoxy-ethyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0483] Intermediate 47B was prepared from Intermediate 47A using Method IX. HRMS (M+H) calcd for C₂₀H₂₁NO₅F: 374.1404; found: 374.1412. ¹H NMR (500 MHz, CDCl₃) δ: 3.71 (t, J=5), 3.80 (t, J=5), 3.85 (s), 3,90 (s), 4.12 (t, J=5), 4.20 (t, J=50, 4.76 (s), 6.27 (s), 6.44 (s), 6.86 (m), 6.99 (m), 7.17 (m), 7.29 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 45.82, 46.37, 48.85, 52.23, 53.00, 53.01, 65.74, 66.14, 93.55, 93.94, 114.33, 115.65, 115.82, 115.91, 116.08, 117.05, 117.11, 121.24, 121.53, 128.41, 128.47, 129.61, 129.66, 129.79, 129.85, 131.70, 131.72, 132.35, 132.37, 157.95, 158.23, 159.68, 159.99, 161.41, 161.45, 163.11, 163.25, 163.36, 163.41, 171.37, 171.60.

[0484] Compound 47: 3-{(4-Fluoro-benzyl)-[2-(4-fluoro-phenoxy)-ethyl]-carbamoyl}-2-hydroxy-acrylic Acid

[0485] Compound 47 was prepared from Intermediate 47B using Method XI. HRMS (M+H) calcd for C₁₉H₁₈NO₅F₂: 378.1153; found: 378.1151. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.71 (m), 3.83 (m), 4.04 (m), 4.12 (m), 4.75 (s), 4.76 (s), 6.34 (s), 6.51 (s), 6.75-7.27 (overlapping m).

EXAMPLE 48

[0486] Intermediate 48A: N-(3-Bromo-4-fluoro-benzyl)-N-methyl-acetamide

[0487] Intermediate 48A was prepared from 3-bromo-4-fluoro-benzoic acid using Methods II and IV. HRMS (M+H) calcd for C₁₀H₁₂BrFNO: 260.0086; found: 260.0085. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.13 (s), 2.14 (s), 2.91 (sO, 2.92 (s), 4.47 (s), 4.50 (s), 7.03-7.43 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.44, 21.80, 33.68, 35.65, 49.61, 53.13, 99.71, 109.05, 109.21, 109.84, 116.45, 116.63, 116.90, 117.07, 126.81, 126.87, 128.64, 128.70, 131.38, 132.96, 134.03, 134.91, 134.94, 157.43, 157.55, 159.39, 159.52, 170.86.

[0488] Intermediate 48B: 3-[(3-Bromo-4-fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0489] Intermediate 48B was prepared from Intermediate 48A using Method IX. HRMS (M+H) calcd for C₁₃H₁₄NO₄FBr: 346.0090; found: 346.0092. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.01 (s), 3.02 (s), 3.70 (s), 3.89 (s), 4.54 (s), 4.59 (s), 6.26 (s), 6.29 (s), 7.10 (m), 7.19 (m), 7.36 (m), 7.44 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.55, 34.95, 49.60, 52.13, 53.01, 92.98, 93.43, 109.32, 109.48, 109.78, 109.95, 116.72, 116.89, 117.04, 117.08, 117.72, 117.21, 127.14, 127.20, 128.62, 128.68, 131.74, 133.02, 133.80, 133.84, 157.68, 159.65, 159.82, 159.97, 163.17, 171.02, 171.21.

[0490] Compound 48: 3-[(3-Bromo-4-fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0491] Compound 48 was prepared from Intermediate 48B using Method XI. HRMS (M−H) calcd for C₁₂H₁₀NO₄BrF: 329.9777; found: 329.9784. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.03 (s), 3.04 (s), 4.55 (s), 4.60 (s), 6.34 (s), 6.36 (s), 7.10 (m), 7.18 (m), 7.37 (m), 7.45 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.75, 35.04, 49.78, 52.23, 93.29, 93.75, 109.38, 109.55, 116.77, 116.95, 117.28, 127.26, 128.66, 128.72, 131.78, 132.76, 133.07, 133.51, 133.54, 157.75, 159.05, 159.72, 165.10, 170.92, 171.12.

EXAMPLE 49

[0492] Intermediate 49A: N-(4-Fluoro-benzyl)-N-[2-(4-fluoro-phenoxy)-ethyl]-acetamide

[0493] Intermediate 49A was prepared from 1-(2-Bromo-ethoxy)-4-fluoro-benzene and 4-fluorobenzylamine using Method VI. HRMS (M+H) calcd for C₁₇H₁₈F₂NO: 306.1351; found: 306.1298. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.13 (s), 2.28 (s), 3.63 (t, J=5), 3.71 (t, J=5), 3.96 (t, J=5), 4.11 (t, J=5), 6.74-7.24 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 21.75, 21.80, 45.78, 47.15, 48.04, 53.18, 66.11, 67.07, 115.24, 115.31, 115.35, 115.41, 115.56, 115.79, 115.81, 115.92, 115.98, 116.10, 127.98, 128.05, 129.64, 129.70, 132.52, 132.54, 133.35, 133.37, 154.28, 154.59, 154.60, 156.39, 156.61, 158.28, 158.52, 161.20, 161.27, 163.16, 163.23, 171.24, 171.35.

[0494] Intermediate 49B: 3-{(4-Fluoro-benzyl)-[2-(4-fluoro-phenoxy)-ethyl]-carbamoyl}-2-hydroxy-acrylic Acid Methyl Ester

[0495] Intermediate 49B was prepared from Intermediate 49A sing Method IX. HRMS (M+H) calcd for C₂₀H₂₀NO₅F: 392.1310; found: 392.1319. Anal calcd for C₂₀H₁₉NO₅F: C, 61.38; H, 4.89; N, 3.57; found: C, 61.28; H, 4.82; N, 3.50. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.70 (t, J=5), 3.80 (t, J=5), 3.85 (s), 3.90 (s), 4.03 (t, J=5), 4.15 (t J=5), 4.74 (s), 4.75 (s), 6.28 (s), 6.42 (s), 6.78 (m), 6.95-7.07 (overlapping m), 7.24 (m), 7.26 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 45.88, 46.39, 48.87, 52.25, 53.01, 53.03, 66.43, 66.77, 93.50, 93.88, 115.292, 115.36, 115.43, 115.66, 115.83, 115.87, 115.93, 115.95, 116.06, 116.11, 116.14, 128.36, 128.43, 129.75, 129.82, 131.63, 132.32, 154.08, 154.36, 156.52, 158.42, 158.58, 159.71, 160.04, 161.47, 163.08, 163.24, 163.38, 163.43, 171.37, 171.63.

[0496] Compound 49: 3-[(4-Fluoro-benzyl)-(2-phenoxy-ethyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0497] Compound 49 was prepared from Intermediate 49B using Method XI. HRMS (M−H) calcd for C₁₉H₁₇NO₅F: 358.1091; found: 358.1098. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.72 (m), 3.82 (m), 4.09 (m), 4.21 (m), 6.35 (s), 6.53 (s), 6.86 (m), 7.04 (overlapping m), 7.17 (m), 7.27 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 45.97, 46.48, 49.05, 52.33, 65.72, 66.04, 93.74, 94.14, 114.33, 115.71, 115.89, 115.99, 116.16, 121.31, 121.60, 128.43, 128.50, 129.63, 129.68, 129.76, 129.83, 129.89, 131.40, 132.05, 157.88, 158.17, 158.81, 159.15, 161.46, 161.50, 163.42, 163.47, 164.65, 164.77, 171.32, 171.52.

EXAMPLE 50

[0498] Intermediate 50A: N-[1-(4-Fluoro-phenyl)-ethyl]-N-methyl-acetamide

[0499] Intermediate 50A was prepared 1-(4-fluoro-phenyl)-ethyl amine using the same method as Intermediate 34A. HRMS (M+H) calcd for C₁₁H₁₅FNO: 196.1138; found: 196.1139. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.44 (d, J=7), 1.57 (d, J=7), 2.11 (s), 2.22 (s), 2.63 (s), 5.05 (q, J=7), 6.02 (q, J=7), 7.00 (overlapping m), 7.23 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 15.76, 17.72, 21.75, 22.31, 27.57, 30.05, 49.40, 55.15, 115.14, 115.31, 115.51, 115.69, 128.11, 128.86, 135.96, 136.46, 160.98, 161.09, 162.933, 163.06, 170.42, 170.63.

[0500] Intermediate 50B: 3-{[1-(4-Fluoro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid Methyl Ester

[0501] Intermediate 50B was prepared from Intermediate 50A using Method IX. HRMS (M+H) calcd for C₁₄H₁₇NO₄F: 282.1142; found: 282.1141. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.52 (d, J=7), 1.63 (d, J=7), 2.71 (s), 2.72 (s), 3.89 (s), 5.24 (q, J=7), 6.03 (q, J=7), 6.24 (s), 6.45 (s), 7.04 (m), 7.26 (m). ¹³C NMR (125 MHz, CDCl₃) δ: 15.81, 17.56, 27.69, 29.47, 49.73, 52.97, 54.19, 93.10, 94.04, 115.45, 115.62, 115.70, 115.87, 128.41, 128.47, 128.91, 128.97, 135.34, 135.37, 159.63, 159.96, 161.22, 163.18, 163.34, 163.43, 170.75.

[0502] Compound 50: 3-{[1-(4-Fluoro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0503] Compound 50 was prepared from Intermediate 50B using Method XI. HRMS (M−H) calcd for C₁₃H₁₃NO₄F: 266.0829; found: 266.0835. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.53 (d, J=7), 1.64 (d, J=7), 2.74 (s), 5.25 (q, J=7), 6.02 (q, J=7), 6.31 (s), 6.52 (s), 7.05 (m), 7.21-7.27 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 15.81, 17.54, 27.94, 29.56, 50.09, 54.42, 93.04, 94.09, 115.52, 115.69, 115.77, 115.90, 115.94, 128.43, 128.50, 128.93, 128.99, 134.59, 135.04, 135.07, 159.08, 159.49, 161.28, 163.24, 165.22, 170.66, 170.71.

EXAMPLE 51

[0504] Intermediate 51A: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-[3-(2-fluoro-phenyl)-propyl]-acetamide

[0505] Intermediate 51A was prepared from 4-(Fluoro-benzyl)-[3-(2-fluoro-phenyl)-propyl]-amine hydrochloride using Method XIV. MS (M+H) calcd for C₂₃H₂₄F₂NO₄: 416.2; found: 416.0. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (300 MHz, CDCl₃) δ: 1.71 (s), 1.73 (s), 1.87 (m), 2.62 (m), 3.28 (m), 3.44 (m), 4.53 (s), 4.58 (s), 6.08 (s), 6.93-7.21 (overlapping m).

[0506] Compound 51: 3-{(4-Fluoro-benzyl)-[3-(2-fluoro-phenyl)-propyl]-carbamoyl}-2-hydroxy-acrylic Acid

[0507] Compound 51 was prepared from Intermediate 51A using Method XVIII. MS (M−H) calcd for C₂₀H₁₈NO₄F₂: 372.12; found: 374.01. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, d₆-MeOD) δ: 1.86 (m), 2.65 (m), 3.34 (m), 3.47 (m), 3.72 (m), 4.61 (s), 4.63 (s), 6.21 (s), 6.29 (s), 6.98-7.26 (overlapping m).

EXAMPLE 52

[0508] Intermediate 52A: 2-(2,2-Dimethyl-5-oxo[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-(2-phenyl-cyclopropylmethyl)-acetamide

[0509] Intermediate 52A was prepared from (4-fluoro-benzyl)-(2-phenyl-cyclopropylmethyl)-amine hydrochloride using Method XIV. MS (M+H) calcd for C₂₄H₂₅FNO₄: 410.2; found: 410.1.

[0510] Compound 52: 3-[(4-Fluoro-benzyl)-(2-phenyl-cyclopropylmethyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0511] Compound 52 was prepared from Intermediate 52A using Method XVIII. MS (M−H) calcd for C₂₁H₁₉NO₄F: 368.13; found: 368.06. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, d₆-MeOD) δ: 0.92 (m), 1.28 (m), 1.85 (m), 3.39-3.65 (overlapping m), 4.73 (s), 6.25 (s), 6.46 (s), 6.92-7.29 (overlapping m). ¹³C NMR (125 MHz, d₆-MeOD) δ: 14.96, 15.19, 22.98, 23.11, 23.41, 23.53, 23.73, 49.73, 49.92, 51.29, 51.99, 52.35, 95.20, 95.24, 116.27, 116.45, 116.51, 116.63, 116.69, 126.64, 126.72, 126.81, 129.35, 129.39, 129.52, 129.58, 130.45, 130.52, 130.84, 130.91, 134.61, 143.28, 143.78, 160.78, 160.82, 162.89, 164.63, 165.51, 165.63, 172.42, 172.95.

EXAMPLE 53

[0512] Intermediate 53A: 2-(2,2-Dimethyl-5-oxo[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-naphthalen-2-ylmethyl-acetamide

[0513] Intermediate 53A was prepared from (4-fluoro-benzyl)-naphthalen-2-ylmethyl-amine hydrochloride using Method XIV. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.73 (s), 1.76 (s), 4.50 (s), 4.66 (s), 4.67 (s), 4.79 (s), 6.21 (s), 6.24 (s), 7.00-7.86 (overlapping m).

[0514] Compound 53: 3-[(4-Fluoro-benzyl)-naphthalen-2-ylmethyl-carbamoyl]-2-hydroxy-acrylic Acid

[0515] Compound 53 was prepared from Intermediate 53A using Method XVIII. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, d₆-MeOD) δ: 4.57 (s), 4.70 (s), 4.77 (s), 4.82 (s), 6.39 (s), 6.42 (s), 7.01-7.85 (overlapping m).

EXAMPLE 54

[0516] Intermediate 54A: 2-(2,2-Dimethl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-N-naphthalen-2-ylmethyl-acetamide

[0517] Intermediate 54A was prepared from methyl-naphthalen-2-ylmethyl-amine hydrochloride using Method XVII. ¹H NMR shows mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.69 (s), 1.76 (s), 3.03 (s), 3.05 (s), 4.75 (s), 4.82 (s), 6.21 (s), 6.22 (s), 7.28-7.85 (overlapping m).

[0518] Compound 54: 2-Hydroxy-3-(methyl-naphthalen-2-ylmethyl-carbamoyl)-acrylic Acid

[0519] Compound 54 was prepared from Intermediate 54A using Method XVIII. MS (M−H) calcd C₁₆H₁₄NO₅: 284.09; found: 284.07. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, d₆-MeOD) δ: 3.33 (s), 3.34 (s), 4.82 (s), 6.40 (s), 6.44 (s), 7.33-7.88 (overlapping m).

EXAMPLE 55

[0520] Intermediate 55A: N-(4-Chloro-phenyl)-2-(2,2-deimethyl-5-oxo-[1,3]-4-ylidene)-N-naphthalen-2-ylmethyl-acetamide

[0521] Intermediate 55A was prepared from (4-chloro-phenyl)-naphthalen-2-ylmethyl-amine hydrochloride using Method XVII. MS (M+H) calcd for C₂₄H₂₁ClNO₄: 422.1; found: 422.1. ¹H NMR (500 MHz, d₆-MeOD) δ: 1.69 (s, 6), 5.15 (s, 2), 5.62 (s, 1), 7.11-7.82 (overlapping m, 11).

[0522] Compound 55: 3-[(4-Chloro-phenyl)-naphthalen-2-ylmethyl-carbamoyl]-2-hydroxy-acrylic Acid

[0523] Compound 55 was prepared from Intermediate 55A using Method XVIII. MS (M−H) calcd for C₂₁H₁₅NO₄Cl: 380.07; found: 380.07. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, DMSO) δ: 5.04 (s), 5.14 (s), 5.59 (br s), 7.23-7.88 (overlapping m).

EXAMPLE 56

[0524] Intermediate 56A: N-(4-Chloro-phenyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(3-phenyl-propyl)-acetamide

[0525] Intermediate 56A was prepared from (4-chloro-phenyl)-(3-phenyl-propyl)-amine hydrochloride using Method XVII. MS (M+H) calcd for C₂₂H₂₃ClNO₄: 400.1; found: 400.1.

[0526] Compound 56: 3-[(4-Chloro-phenyl)-(3-phenyl-propyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0527] Compound 56 was prepared from Intermediate 56A using Method XVIII. MS (M−H) calcd for C₁₉H₁₇NO₄Cl: 358.08; found: 358.02.

EXAMPLE 57

[0528] Intermediate 57A: N,N-Bis(4-chloro-benzyl)-acetamide

[0529] Intermediate 57A was prepared from 4-chlorobenzylamine and 4-chlorobenzylbromide using the same method as intermediate 43A. HRMS (M+H) calcd for C₁₆H₁₆Cl₂NO: 308.0609; found: 308.0611. ¹H NMR (500 MHz, CDCl₃) δ: 2.20 (s, 3), 4.39 (s, 2), 4.52 (s, 2), 7.07 (d, 2, J=8), 7.14 (d, 2, J=8), 7.27 (d, 2, J=8), 7.34 (d, 2, J=8). ¹³C NMR (125 MHz, CDCl₃) δ: 21.70, 47.41, 50.31., 127.78, 128.83, 129.25, 129.72, 133.41, 133.66, 134.67, 135.63, 171.07.

[0530] Intermediate 57B: 3-[Bis-(4-chloro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid Methyl Ester

[0531] Intermediate 57B was prepared from Intermediate 57A using Method IX. HRMS (M+H) calcd for C₁₉H₁₈NO4Cl₂: 394.0613; found: 394.0602. ¹H NMR (500 MHz, CDCl₃) δ: 3.87 (s, 3), 4.46 (s, 2), 4.58 (s, 2), 6.30 (s, 1), 7.08 (d, 2, J=8), 7.16 (d, 2, J=8), 7.31 (d, 2, J=8), 7.34 (d, 2, J=8). ¹³C NMR (125 MHz, CDCl₃) δ: 47.54, 49.50, 53.05, 93.21, 128.10, 129.04, 129.34, 129.65, 133.79, 133.66, 134.09, 134.58, 160.39, 163.04, 171.46.

[0532] Compound 57: 3-[Bis-(4-chloro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0533] Compound 57 was prepared from Intermediate 57B using Method XVIII. HRMS (M−H) calcd for C₁₈H₁₄NO₄Cl₂: 378.0300; found: 378.0297. Anal calcd for C₁₈H₁₅NO₄Cl₂: C 56.86, H 3.97; N 3.68; found: C 57.04; H 4.02; N 3.60. H NMR (500 MHz, DMSO) δ: 4.62 (s, 2), 4.69 (s, 2), 6.23 (s, 1), 7.21-7.44 (overlapping m, 8). ¹³C NMR (125 MHz, DMSO) δ: 48.14, 49.65, 93.21, 128.31, 128.39, 128.63, 129.64, 131.90, 131.94, 135.68, 135.76, 160.39, 163.24, 171.36.

EXAMPLE 58

[0534] Intermediate 58A:(3-Chloro-4-fluoro-benzyl)-methyl-amine

[0535] Intermediate 58A was formed from 4-fluoro-3-chloro-benzaldehyde using Method III. HRMS (M+H) calcd for C₈H₁₀NClF: 174.0486; found: 174.0481. ¹H NMR (500 MHz, CDCl₃) δ: 2.43 (s, 3), 3.69 (s, 2), 7.07 (m, 1), 7.17 (m, 1), 7.37 (m, 1). ¹³C NMR (125 MHz, CDCl₃) δ: 35.96, 54.87, 116.27, 116.44, 120.68, 120.82, 127.70, 127.75, 130.19, 137.32, 137.35, 156.15, 158.11.

[0536] Intermediate 58B: N-(3-Chloro-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0537] Intermediate 58B was prepared from Intermediate 58A using Method XVII. HRMS (M+H) calcd for C₁₅H₁₆NO₄ClF: 328.0752; found: 328.0755. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.72 (s), 1.74 (s), 2.96 (s), 3.01 (s), 4.53 (s), 4.58 (s), 6.09 (s), 6.16 (s), 7.06-7.34 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 26.78, 26.85, 33.28, 35.37, 49.71, 52.88, 96.68, 96.87, 113.89, 113.96, 116.65, 116.82, 117.03, 117,19, 121.11, 121.26, 121.67, 121.81, 126.33, 126.39, 127.95, 128.01, 128.77, 130.20, 133.99, 134.02, 144.85, 144.95, 156.55, 158.53, 162.31, 162.42, 164.08, 164.30.

[0538] Compound 58: 3-[(3-Chloro-4-fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0539] Compound 58 was prepared from Intermediate 58B using Method XVIII. HRMS (M−H) calcd for C₁₂H₁₀NO₄ClF: 286.0282; found: 286.0281. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.03 (s), 3.04 (s), 4.55 (s), 4.60 (s), 6.34 (s), 6.37 (s), 7.10-7.32 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.74, 35.03, 49.89, 52.32, 93.17, 93.63, 116.92, 117.08, 117.27, 117.44, 121.39, 121.53, 126.36, 126.42, 127.81, 127.87, 128.91, 130.22, 133.13, 133.16, 156.77, 158.75, 159.09, 159.27, 164.97, 170.95, 171.16.

EXAMPLE 59

[0540] Intermediate 59A: (3,4-Difluoro-benzyl)-methyl-amine; hydrochloride

[0541] Intermediate 59A was prepared from 3,4-difluorobenzaldehyde using Method III. HRMS (M+H) calcd for C₈H₁₀NF₂ 158.0781; found: 158.0783. ¹H NMR (500 MHz, d₆-MeOD) δ: 1.18 (s, 3), 2.66 (s, 2), 5.82 (m, 2), 5.98 (m, 1). ¹³C NMR (125 MHz, d₆-MeOD) δ: 31.74, 50.87, 117.67, 117.69, 117.80, 118.82, 118.93, 118.97, 126.71, 126.75, 126.80, 128.49, 128.54, 128.58, 149.07, 149.19, 149.80, 149.92, 151.06, 151.18, 151.80, 151.92.

[0542] Intermediate 59B: N-(3,4-Difluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0543] Intermediate 59B was prepared from Intermediate 59A using Method XVII. HRMS (M+H) calcd for C₁₅H₁₆NO₄F₂: 312.1048; found: 312.1042. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.70 (s), 1.73 (s), 1.74 (s), 2.97 (s), 3.02 (s), 4.53 (s), 4.58 (s), 6.09 (s), 6.16 (s), 7.00-7.13 (overlapping m).

[0544] Compound 59: 3-[(3,4-Difluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0545] Compound 59 was prepared from Intermediate 59B using Method XVIII. HRMS (M−H) calcd for C₁₂H₁₀NO₄F₂: 270.0578; found: 270.0581. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.04 (s), 4.55 (s), 4.61 (s), 6.34 (s), 6.37 (s), 6.90-7.19 (overlapping m).

EXAMPLE 60

[0546] Intermediate 60A: (4-Fluoro-3-methoxy-benzyl)-methyl-amine

[0547] Intermediate 60A was prepared from 4-fluoro-3-methoxybenzaldehyde using Method III. HRMS (M+H) calcd for C₉H₁₃NOF: 170.0981; found: 170.0984. ¹H NMR (500 MHz, CDCl₃) δ: 2.44 (s, 3), 3.69 (s, 2), 3.88 (s, 3), 6.80 (m, 1), 6.95-7.01 (overlapping m, 2). ¹³C NMR (125 MHz, CDCl₃) δ: 36.06, 55.76, 56.17, 113.17, 115.54, 115.69, 120.25, 120.30, 136.52, 136.55, 147.49, 147.57, 150.53, 152.47.

[0548] Intermediate 60B: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-3-methoxy-benzyl)-N-methyl-acetamide

[0549] Intermediate 60B was prepared from Intermediate 60A using Method XVII. HRMS (M+H) calcd for C₁₆H₁₉NO₅F: 324.1247; found: 324.1239. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.69 (s), 1.72 (s), 2.97 (s),2.99 (s), 3.85 (s), 3.86 (s), 4.52 (s), 4.58 (s), 6.13 (s), 6.16 (s), 6.79-7.04 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 26.77, 26.84, 33.36, 35.12, 50.25, 53.50, 56.34, 96.99, 97.06, 111.69, 113.45, 113.79, 113.83, 115.82, 115.96, 116.33, 116.48, 118.78, 118.83, 120.61, 120.67, 132.43, 132.46, 133.22, 133.25, 144.74, 144.80, 147.81, 147.89, 148.14, 150.96, 152.92, 162.42, 162.51, 163.94, 164.31.

[0550] Compound 60: 3-[(4-Fluoro-3-methoxy-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0551] Compound 60 was prepared from Intermediate 60B using Method XVIII. HRMS (M−H) calcd for C₁₃H₁₃NO₅F: 282.0778; found: 282.0774. Anal calcd for C₁₃H₁₄NO₅F: C, 55.12; H, 4.98; N, 4.94; found: C, 55.15; H, 5.05; N, 4.81. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, DMSO) δ: 2.97 (s), 3.02 (s), 3.83 (s), 4.58 (s), 4.65 (s), 6.26 (s), 6.28 (s), 6.72-7.20 (overlapping m). ¹³C NMR (125 MHz, DMSO) δ: 33.48, 34.70, 49.36, 51.85, 55.77, 93.00, 93.10, 112.34, 113.26, 115.61, 115.75, 115.85, 115.99, 118.26, 118.31, 119.67, 119.73, 133.34, 146.94, 147.03, 147.09, 147.18, 149.78, 151.72, 160.00, 163.42, 170.61, 170.93.

EXAMPLE 61

[0552] Intermediate 61A: (4-Fluoro-3-methyl-benzyl)-methyl-amine

[0553] Intermediate 61A was prepared from 4-fluoro-3-methyl-benzylbromide using Method I. LC/MS (M+H) calcd for C₉H₁₃NF: 154.1; found: 154.1. ¹H NMR (500 MHz, CDCl₃) δ: 2.25 (s, 3), 2.44 (s, 3), 3.67 (s, 2), 6.94 (m, 1), 7.08 (m, 1), 7.14 (m).

[0554] Intermediate 61B: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-3-methyl-benzyl)-N-methyl-acetamide

[0555] Intermediate 61B was prepared from Intermediate 61A using Method XVII. HRMS (M+H) calcd for C₁₆H₁₉NO₄F: 308.1298; found: 308.1302. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.70 (s), 1.73 (s), 2.24 (s), 2.25 (s), 2.95 (s), 2.98 (s), 4.50 (s), 4.57 (s), 6.14 (s), 6.16 (s), 6.91-7.11 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 14.52, 14.55, 14.60, 26.79, 26.86, 33.22, 35.12, 49.92, 53.26, 97.03, 97.28, 113.74, 113.84, 114.95, 115.13, 115.34, 115.52, 125.05, 125.18, 125.48, 125.55, 125.60, 127.16, 127.22, 129.59, 129.63, 131.32, 131.36, 131.45, 132.29, 144.68, 144.76, 159.83, 161.77, 162.47, 162.58, 163.88, 164.25.

[0556] Compound 61: 3-[(4-Fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0557] Compound 61 was prepared from Intermediate 61B using Method XVIII. HRMS (M−H) calcd for C₁₃H₁₃NO₄F: 266.0828; found: 266.0826. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 2.26 (s), 3.01 (s), 4.52 (s), 4.59 (s), 6.36 (s), 6.39 (s), 6.98-7.29 (overlapping m). ¹³C NMR (125 Hz, CDCl₃) δ: 14.60, 33.64, 34.84, 50.17, 52.78, 93.47, 93.64, 115.23, 115.41, 115.55, 115.73, 125.37, 125.51, 125.69, 125.88, 127.05, 129.79, 130.64, 131.19, 131.37, 159.10, 160.03, 160.01, 165.16, 170.81, 171.06.

EXAMPLE 62

[0558] Intermediate 62A: (3-Chlorobenzyl)-methylamine

[0559] Intermediate 62A was prepared from 3-chloro-benzylbromide using Method I. LC/MS (M+H) calcd for C₈H₁₁NCl; 156.1; found: 156.1. ¹H NMR (500 MHz, CDCl₃) δ: 2.44 (s, 3), 3.72 (s, 2), 7.23 (m, 3), 7.32 (s, 1)

[0560] Intermediate 62B: N-(3-Chloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0561] Intermediate 62B was prepared from Intermediate 62A using Method XVII. HRMS (M+H) calcd for C₁₅H₁₇NO₄Cl; 310.0846; found: 310.0845. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.63 (s), 1.68 (s), 2.92 (s), 2.96 (s), 4.50 (s), 4.56 (s), 6.05 (s), 6.11 (s), 7.09-7.23 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 27.03, 27.12, 33.63, 35.65, 50.42, 53.68, 97.15, 97.41, 114.07, 114.16, 125.04, 126.56, 126.94, 128.02, 128.30, 128.37, 130.23, 130.52, 134.84, 135.27, 138.56, 139.19, 144.94, 145.06, 162.61, 162.73, 164.35, 164.65.

[0562] Compound 62: 3-[(3-Chloro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0563] Compound 62 was prepared from Intermediate 62B using Method XVIII. HRMS (M−H) calcd for C₁₂H₁₁NO₄Cl; 268.0377; found: 268.0384. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.04 (s), 4.57 (s), 4.63 (s), 6.35 (s), 6.37 (s), 7.14-7.32 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) 33.83, 35.09, 50.37, 52.85, 93.26, 93.55, 124.75, 129.09, 126.77, 128.00, 128.13, 128.22, 128.39, 128.44, 130.19, 130.29, 130.47, 134.77, 135.13, 137.42, 138.06, 159.22, 164.93, 171.01, 171.24.

EXAMPLE 63

[0564] Intermediate 63A: (4′-Fluoro-biphenyl-3-ylmethyl)-methyl-amine

[0565] Intermediate 63A was prepared from 4′-fluoro-biphenyl-3-carbaldehyde using Method III. LC/MS (M+H) calcd C₁₄H₁₅NF; 216.1; found: 216.2. ¹H NMR (500 MHz, CDCl₃) δ: 2.50 (s, 3), 3.82 (s, 2), 7.11 (m, 2), 7.30 (m, 1), 7.38-7.57 (overlapping m, 5). ¹³C NMR (125 MHz, CDCl₃) δ: 36.17, 56.13, 115.51, 115.68, 125.71, 126.88, 127.14, 128.71, 128.78, 128.91, 137.29, 140.41, 140.81.

[0566] Intermediate 63B: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4′-fluoro-biphenyl-3-ylmethyl)-N-methyl-acetamide

[0567] Intermediate 63B was prepared from Intermediate 63A using Method XVII. HRMS (M+H) calcd for C₂₁H₂₁NO₄F: 370.1455; found: 370.1450. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.67 (s), 1.73 (s), 3.03 (s), 4.65 (s), 4.72 (s), 6.18 (s), 6.19 (s), 7.10-7.54 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 26.75, 26.85, 33.49, 35.30, 50.60, 65.91, 97.11, 97.35, 113.75, 113.83, 115.56, 115.67, 115.73, 115.84, 125.10, 125.43, 126.29, 126.59, 126.79, 127.15, 128.77, 128.83, 129.18, 129.49, 136.83, 136.99, 137.51, 140.76, 141.11, 144.70, 162.56, 164.03, 164.45.

[0568] Compound 63: 3-[(4′-Fluoro-biphenyl-3-ylmethyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0569] Compound 63 was prepared from Intermediate 63B using Method XVIII. HRMS (M−H) calcd for C₁₈H₁₅NO₄F; 328.0985; found: 328.0989. Anal. Calcd for C₁₈H₁₆NO₄F: C, 65.64; H, 4.89; N, 4.25; found: C, 65.39; H, 5.27; N, 4.00.

EXAMPLE 64

[0570] Intermediate 64A: Methyl-(3-phenoxy-benzyl)-amine

[0571] Intermediate 64A was prepared from 3-phenoxy-benzylbromide using Method I. LC/MS (M+H) calcd for C₁₄H₁₆NO: 214.1; found: 214.2. ¹H NMR (500 MHz, CDCl₃) δ: 2.45 (s, 3), 3.74 (s, 2), 6.90 (m, 1), 7.00-7.35 (overlapping m, 8).

[0572] Intermediate 64B: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-N-(3-phenoxy-benzyl)-acetamide

[0573] Intermediate 64B was prepared from Intermediate 64A using Method XVII. LC/MS (M+H) calcd C₂₁H₂₂NO₅: 368.1; found:368.2. HRMS calcd for C₂₁H₂₂NO₅: 368.1498; found: 368.1498. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.69 (s), 1.72 (s), 2.99 (s), 3.01 (s), 4.55 (s), 4.64 (s), 6.13 (s), 6.17 (s), 6.85-7.36 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 26.78, 26.84, 33.42, 39.32, 50.31, 53.66, 97.04, 97.28, 113.76, 113.83, 116.98, 117.80, 117.94, 118.59, 118.78, 119.03, 121.12, 122.92, 123.33, 123.61, 129.80, 129.88, 130.02, 130.31, 138.28, 138.91, 144.70, 156.78, 157.11, 157.48, 157.99, 162.55, 164.01, 164.35.

[0574] Compound 64: 2-Hydroxy-3-[methyl-(3-phenoxy-benzyl)-carbamoyl]-acrylic Acid

[0575] Compound 64 was prepared from Intermediate 64B using Method XVIII. LC/MS (M+H) calcd for C₁₈H₁₈NO₅: 328.1; found: 328.1. HRMS (M−H) calcd for C₁₈H₁₆NO₅: 326.1029; found: 326.1034. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.02 (s), 3.03 (s), 4.55 (s), 4.63 (s), 6.35 (s), 6.80-7.37 (overlapping m).

EXAMPLE 65

[0576] Intermediate 65A: (3,4-Dimethylbenzyl)-methylamine

[0577] Intermediate 65A was prepared from 3,4-dimethylbenzaldehyde using Method III. HRMS (M+H) calcd for C₁₀H₁₆N; 150.1282; found: 150.1287. ¹H NMR (500 MHz, CDCl₃) δ: 2.25 (s, 3), 2.27 (s, 3), 2.45 (s, 3), 3.69 (s, 2), 7.04-7.11 (m, 3). ¹³C NMR (125 MHz, CDCl₃) δ: 19.43, 19.74, 36.08, 55.88, 125.62, 129.59, 129.61, 135.18, 136.57, 137.63.

[0578] Intermediate 65B: N-(3,4-Dimethyl-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0579] Intermediate 65B was prepared from Intermediate 65A using Method XVII. LC/MS (M+H) calcd for C₁₇H₂₂NO₄: 304.2; found: 304.3. HRMS (M+H) calcd for C₁₇H₂₂NO₄; 304.1549; found: 304.1552.

[0580] Compound 65: 3-[(3,4-Dimethyl-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0581] Compound 65 was prepared from Intermediate 65B using Method XVIII. LC/MS (M+H) calcd for C₁₄H₁₈NO₄; 264.1; found: 264.3.

EXAMPLE 66

[0582] Intermediate 66A: (4-Methoxy-3-methylbenzyl)-methylamine

[0583] Intermediate 66A was prepared from 4-methoxy-3-methyl-benzaldehyde using Method III. HRMS (M+H) calcd for C₁₀H₁₆NO; 166.1232; found: 166.1235. ¹H NMR (500 MHz, CDCl₃) δ: 2.23 (s, 3), 2.46 (s, 3), 3.67 (s, 2), 3.82 (s, 3), 6.77 (m, 1), 7.10 (m, 2). ¹³C NMR (125 MHz, CDCl₃) δ: 16.21, 35.97, 55.37, 55.59, 109.74, 126.53, 130.75, 131.84, 156.84.

[0584] Intermediate 66B: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-methoxy-3-methyl-benzyl)-N-methyl-acetamide

[0585] Intermediate 66B was prepared from Intermediate 66A using Method XVII. LC/MS (M+H) calcd for C₁₇H₂₂NO₅: 320.1; found: 320.1. HRMS (M+H) calcd for C₁₇H₂₂NO₅: 320.1498; found: 320.1490. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.70 (s), 1.73 (s), 2.19 (s), 2.95 (s), 2.98 (s), 3.80 (s), 3.81 (s), 4.48 (s), 4.55 (s), 6.16 (s), 6.19 (s), 6.75-7.08 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 16.20, 16.29, 26.80, 26.86, 33.11, 34.11, 34.94, 49.94, 53.42, 55.36, 55.41, 97.40, 97.71, 109.83, 110.06, 113.63, 113.74, 125.17, 126.93, 127.27, 127.46, 128.41, 129.02, 130.78, 144.43, 144.51, 157.26, 157.42, 162.55, 162.67, 163.77, 164.22.

[0586] Compound 66: 2-Hydroxy-3-[(4-methoxy-3-methyl-benzyl)-methyl-carbamoyl]-acrylic Acid

[0587] Compound 66 was prepared from Intermediate 66B using Method XVIII. LC/MS calcd for C₁₄H₁₈NO₅: 280.1; found: 280.3.

EXAMPLE 67

[0588] Intermediate 67A: (4-Chloro-3-fluoro-benzyl)-methyl-amine

[0589] Intermediate 67A was prepared from 4-chloro-3-fluoro-benzaldehyde using Method III. LC/MS (M+H) calcd for C₈H₁₀NClF; 174.0; found: 174.1. ¹H NMR (500 MHz, CDCl₃) δ: 2.43 (s, 3), 3.72 (s, 2), 7.05 (m, 1), 7.15 (m, 1), 7.33 (m, 1). ¹³C NMR (125 MHz, CDCl₃) δ: 35.92, 54.94, 116.08, 116.25, 119.13, 119.27, 124.35, 124.38, 130.39, 141.24, 141.29, 157.12, 159.10.

[0590] Intermediate 67B: N-(4-Chloro-3-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0591] Intermediate 67B was prepared from Intermediate 67A using Method XVII. LC/MS (M+H) calcd for C₁₅H₁₆NO₄ClF: 328.1; found: 328.1. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.70 (s), 1.74 (s), 2.98 (s), 3.03 (s), 4.55 (s), 4.60 (s), 6.08 (s), 6.17 (s), 7.08 (overlapping m), 7.34 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 26.78, 26.85, 33.42, 35.46, 49.94, 53.04, 96.54, 96.74, 113.91, 113.98, 114.74, 114.91, 116.15, 116.32, 120.01, 120.15, 120.42, 120.55, 122.88, 122.91, 124.46, 124.49, 130.76, 131.20, 137.24, 137.88, 137.93, 144.95, 145.06, 157.22, 157.47, 159.20, 159.46, 162.29, 162.42, 164.10, 164.32.

[0592] Compound 67: 3-[(4-Chloro-3-fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0593] Compound 67 was prepared from Intermediate 67B using Method XVIII. LC/MS calcd for C₁₂H₁₂NO₄FC1: 288.0; found: 288.1.

EXAMPLE 68

[0594] Intermediate 68A: Benzo[1,3]dioxol-5-ylmethyl-methyl-amine

[0595] Intermediate 68A was prepared from benzo[1,3]dioxole-5-carbaldehyde using Method III. LC/MS (M+H) calcd for C₉H₁₂NO₂; 166.1; found: 166.1. ¹H NMR (500 MHz, CDCl₃) δ: 2.42 (s, 3), 3.65 (s, 2), 5.95 (d, 2), 6.75-6.86 (overlapping m, 3).

[0596] Intermediate 68B: N-Benzo[1,3]dioxol-5-ylmethyl-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0597] Intermediate 68B was prepared from Intermediate 68A using Method XVII. LC/MS (M+H) calcd for C₁₆H₁₈NO₆: 320.1; found: 320.1.

[0598] Compound 68: 3-(Benzo[1,3]dioxol-5-ylmethyl-methyl-carbamoyl)-2-hydroxy-acrylic Acid

[0599] Compound 68 was prepared from Intermediate 68B using Method XVIII. LC/MS calcd for C₁₃H₁₄NO₆: 280.1; found: 280.1. ¹H NMR and ¹³C NMR show a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.00 (s), 4.48 (s), 4.55 (s), 5.95 (s), 5.96 (s), 6.33 (s), 6.39 (s), 6.61-6.79 (overlapping m). ¹³C NMR (125 MHz, CDCl₃) δ: 33.51, 34.70, 50.58, 53.17, 93.31, 93.44, 101.20, 101.28, 101.35, 107.13, 108.36, 108.51, 108.66, 120.22, 121.59, 121.89, 129.04, 129.75, 147.35, 147.56, 148.15, 148.39, 159.28, 159.36, 164.85, 170.85, 171.10.

EXAMPLE 69

[0600] Intermediate 69A: (2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-methyl-amine

[0601] Intermediate 69A was prepared from 2,2-difluoro-benzo[1,3]dioxole-5-carbaldehyde using Method III. LC/MS (M+H) calcd for C₉H₁₀NO₂F₂: 202.1; found: 202.1. ¹H NMR (500 MHz, CDCl₃) δ: 2.44 (s, 3), 3.73 (s, 2), 6.97-7.09 (overlapping m, 3). ¹³C NMR (125 MHz, CDCl₃) δ: 35.85, 55.59, 109.05, 109.42, 123.11, 129.63, 131.66, 133.68, 136.50, 142.71, 143.93.

[0602] Intermediate 69B: N-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0603] Intermediate 69B was prepared from Intermediate 69A using Method XVII. LC/MS (M+H) calcd for C₁₆H₁₆NO₆F₂: 356.1; found: 356.1. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.70 (s), 1.74 (s), 2.97 (s), 3.01 (s), 4.56 (s), 4.60 (s), 6.11 (s), 6.15 (s), 6.90-7.06 (overlapping m).

[0604] Compound 69: 3-[(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0605] Compound 69 was prepared from Intermediate 69B using Method XVIII. LC/MS calcd for C₁₃H₁₂NO₆F₂: 316.1; found: 316.1. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 3.02 (s), 4.57 (s), 4.62 (s), 6.34 (s), 6.89-7.06 (overlapping m).

EXAMPLE 70

[0606] Intermediate 70A: (4-Chlorophenyl)-(4-fluorobenzyl)-amine

[0607] Intermediate 70A was prepared from N-(4-chlorophenyl)-4-fluorobenzamide using Method II, step 2. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 4.28 (2H, s, NCH₂), 6.54 (2H, d, J=9 Hz, aromatics), 7.03 (2H, broad t, aromatics), 7.12 (2H, d, J=9 Hz, aromatics), 7.31 (2H, m, aromatics). MS (ESI⁺) (m/z) 236 (M+H⁺).

[0608] Intermediate 70B: N-(4-Chloro-phenyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-acetamide

[0609] Intermediate 70B was prepared from Intermediate 70A using Method XIV. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.72 (6H, s, CH₃), 4.88 (2H, s, NCH₂), 5.63 (1H, s, CH), 6.94 (4H, m, aromatics), 7.19 (2H, m, aromatics), 7.32 (2H, m, aromatics). HRMS (MAB N₂) calculated for C₂₀H₁₇ClFNO₄ [M⁺]: 389.083014: found: 389.084846. Anal. Calcd for C₂₀H₁₇ClFNO₄: C, 61.63; H, 4.40; N 3.59 Found: C 61.42, H 4.45, N 3.58

[0610] Compound 70 : 3-[(4-Chloro-phenyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0611] Compound 70 was prepared from Intermediate 70B using Method XVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 4.89 (2H, s, NCH₂), 5.76 (1H, s, CH), 6.91 (2H, d, J=9 Hz, aromatics), 6.98 (2H, ˜t, aromatics), 7.16 (2H, m, aromatics), 7.35 (2H, d, J=9 Hz, aromatics). HRMS (MAB N₂) calculated for C₁₇H₁₃ClFNO₄ [M⁺]: 349.051714: found: 349.050812.

EXAMPLE 71

[0612] Intermediate 71A: N-(4-Chloro-phenyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-methyl-benzyl)-acetamide

[0613] A solution of (Z)-2,2-dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolan-4-one (0.553 g, 2.90 mmol) in dry dichloromethane (5 ml) was added dropwise to a cold (0-5° C.) solution of (4-chlorophenyl)-(4-methylbenzyl)-amine (0.545 g, 2.35 mmol) (Ballistreri et al., J. Org. Chem., 41, 1976, 3364), pyridine (0.35 ml) and a small crystal of 4-N,N-dimethylaminopyridine in dry dichloromethane (10 ml). After 30 min, the cooling bath was removed and the resulting clear solution was stirred at 22° C. for another 30 min. The reaction mixture was then diluted wih ethyl acetate, washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent in vacuo, filtration of the residue on a short silica gel pad (elution-toluene ethyl acetate; 85: 15) followed by crystallization from ethyl acetate-hexane gave 0.794 g (87%) of the title amide as white needles: mp 149° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.72 (6H, s, CH₃), 2.31 (3H, s, CH₃), 4.88 (2H, s, NCH₂), 5.64 (1H, s, CH), 6.93 (2H, d, J=8.5 Hz, aromatics), 7.08 (4H, m, aromatics), 7.3 (2H, d, J=8.5 Hz, aromatics). Anal. Calcd for C₂₁H₂₀ClNO₄: C, 65.37; H, 5.22; N 3.63. Found: C 65.22, H 5.25, N 3.52

[0614] Compound 71: 3-[(4-Chloro-phenyl)-(4-methyl-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0615] Compound 71 was prepared from Intermediate 71A using Method XVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm) 2.32 (3H, s, CH₃), 4.88 (2H, s, NCH₂), 5.76 (1H, S, CH), 6.92 (2H, d, J=8.6 Hz, aromatics), 7.08 (4H, m, aromatics), 7.33 (2H, d, J=8.6 Hz, aromatics). HRMS (MAB N₂) calculated for C₁₈H₁₆ClNO₄ [M⁺]: 345.076786: found: 345.078285.

EXAMPLE 72

[0616] Intermediate 72A: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-(4-fluoro-phenyl)-acetamide

[0617] Acylation of (4-fluorobenzyl)-(4-fluorophenyl)-amine (Pombrik, S. I. et al., Izv. Akad. Nauk. SSSR Ser. Khim., 6, 1982, 1289-1294) with (Z)-2,2-dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolan-4-one as described in the preparation of Intermediate 71A gave the title amide as a syrup. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.72 (6H, s, CH₃), 4.88 (2H, s, NCH₂), 5.29 (1H, s, CH), 6.94 (4H, m, aromatics), 7.03 (2H, m, aromatics), 7.19 (2H, m, aromatics). HRMS (MAB N₂₎ calculated for C₂₀H₁₇F₂NO₄ [M^(+]): 373.112565: found: 373.112320.

[0618] Compound 72: 3-[(4-Fluoro-benzyl)-(4-fluoro-phenyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0619] Compound 72 was prepared from Intermediate 72A using Method XVIII. ¹HNMR 400 MHz (DMSO-d₆) δ (ppm) 4.93 (2H, s, NCH₂), 5.54 (1H, s, CH), 7.11 (2H, m, aromatics), 7.2-7.37 (6H, m, aromatics). HRMS (MAB N₂) calculated for C₁₇H₁₃F₂NO₄ [M⁺]: 333.08127: found: 333.08220.

EXAMPLE 73

[0620] Intermediate 73A: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-phenyl)-N-(4-methyl-benzyl)-acetamide

[0621] Acylation of (4-fluorophenyl)-(4-methylbenzyl)-amine (Pombrik, S. I. et al., Izv. Akad. Nauk. SSSR Ser. Khim., 10, 1981, 2406-2408) with (Z)-2,2-dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolan-4-one as described in the preparation of Intermediate 71A gave the title amide as a syrup. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.72 (6H, s, CH₃), 2.31 (3H, s, CH₃) 4.87 (2H, s, NCH₂), 5.63 (1H, s, CH), 6.93-7.11 (8H, m, aromatics). HRMS (MAB N₂₎ calculated for C₂₁H₂₀FNO₄ [M^(−]): 369.137637: found: 369.137900.

[0622] Compound 73: 3-[(4-Fluoro-phenyl)-(4-methyl-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0623] Compound 73 was prepared from Intermediate 73A using Method XVIII. ¹HNMR 400 MHz δ (ppm): 2.32 (3H, s, CH₃), 4.87 (2H, s, NCH₂), 5.30 (1H, s, CH), 6.96 (2H, m, aromatics), 7.0-7.2 (6H, m, aromatics). HRMS (MAB N₂) calculated for C₁₈H₁₆FNO₄ [M⁺]: 329.106336: found: 329.106590, δ-0.8 ppm.

EXAMPLE 74

[0624] Intermediate 74A: N-(4-Fluorobenzyl)-furfurylamine

[0625] Intermediate 74A was prepared from 2-furoyl chloride and 4-fluorobenzylamine using Method II. ¹HNMR 400 MHz (C₆D₆) δ (ppm): 3.49 (2H, s, NCH₂), 3.61 (2H, s, NCH₂), 6.08 (1H, broad s, CH furyl), 6.21 (1H, broad s, CH furyl), 6.92 (2H, broad t, aromatics), 7.11 (2H, m, aromatic), 7.23 (H, broad s, CH furyl). Anal. Calcd for C₁₂H₁₀FNO₂: C 70.23, H 5.89, N 6.82. Found: C 70.04; H 6.03, N 6.77.

[0626] Intermediate 74B: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-furan-2-ylmethyl-acetamide

[0627] Intermediate 74B was prepared from Intermediate 74A using Method XIV. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 1.74 and 1.77 (6H, 2 s, CH₃), 4.43, 4.61, 4.62 and 4.64 (4H, 4 s, 2×NCH₂), 6.14, 6.21, 6.29, 6.35 and 6.37 (3H, 5 broad s, CH and CH of furyl), 7.04 (2H, m, aromatics) 7.17 (2H, m, aromatics), 7.36 and 7.4 (1H, 2 s, CH of furyl). HRMS (MAB N₂₎ calculated for C₁₉H₁₈FNO₅ [M^(+]): 359.116901: found: 359.117325. Anal. Calcd for C₁₉H₁₈FNO₅: C, 63.51; H, 5.05; N 3.90. Found: C 63.87, H 5.17, N 3.74.

[0628] Compound 74: 3-[(4-Fluoro-benzyl)-furan-2-ylmethyl-carbamoyl]-2-hydroxy-acrylic Acid

[0629] Compound 74 was prepared from Intermediate 74B using Method XVIII. ¹HNMR 400 MHz (DMSO-d₆) 6 (ppm): mixture of rotamers; 4.6, 4.64, 4.65 and 4.69 (4H, 4 s, 2×NCH₂), 6.18 and 6.48 (1H, 2 s, CH), 6.34-6.41 (2H, m, CH of furyl), 7.13-7.32 (4H, m, aromatics), 7.59 and 7.63 (1H, 2s, CH of furyl), 13.67 (1H, broad, OH), 14.24 and 14.32 (1H, 2 broad s, OH). Anal. Calcd for C₁₆H₁₄FNO₅: C 60.19; H 4.42; N 4.39. Found:C 60.15, H 4.21, N4.30

EXAMPLE 75

[0630] Intermediate 75A: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-furan-2-ylmethyl-N-methyl-acetamide

[0631] Intermediate 75A was prepared from N-ethylfurfuryl-amine using Method XIV. Solid: mp 83-86° C. (hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers 1.63 (6H, s, CH₃), 3.03 and 3.1 (3H, 2 s, NCH₃), 4.52 and 4.65 (2H, 2 s, NCH₂), 6.1-6.4 (3H, m, CH and furyl CH), 7.38 and 7.4 (1H, 2 s, furyl CH). MS (ESI⁺) (m/z) 266 (M+H⁺). Anal. Calcd for C₁₃H₁₅NO₅: C 58.86, H 5.69, N 5.28. Found:C 59.02, H 5.52, N 5.12.

[0632] Compound 75: 3-(Furan-2-ylmethyl-methyl-carbamoyl)-2-hydroxy-acrylic Acid

[0633] Compound 75 was prepared from Intermediate 75A using Method XVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 3.0 (3H, s, NCH₃), 4.5 and 4.7 (2H, 2 s, NCH₂), 6.3-6.6 (3H, m, CH and furyl CH), 7.41 (1H, s, furyl CH). MS (ES⁻) (m/z) 224 (M−H)⁻. Anal. Calcd for C₁₀H₁₁NO₅: C 53.33; H 4.92; N 6.22. Found: C 53.43, H 5.0, N 5.92

EXAMPLE 76

[0634] Intermediate 76A: N-(4-Fluorobenzyl)-3-chloro-4-methoxy-benzylamine

[0635] Intermediate 76A was prepared from 4-fluorobenzoyl chloride and 3-chloro-4-methoxy-benzylamine using Method II. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.71 (2H, s, NCH₂), 3.75 (2H, s, NCH₂), 3.89 (3H, s, OCH₃), 6.89 (1H, d, J=8.2 Hz, CH), 7.02 (2H, m, aromatics), 7.2 (1H, dd, J=2.1 Hz and J=8.2 Hz, aromatic), 7.31 (2H, m, aromatics), 7.36 (1H, d, J=2.1 Hz, aromatic). HRMS (MAB N₂) calculated for C₁₅H₁₅ClFNO [M^(+]): 279.08262: found: 279.08157.

[0636] Intermediate 76B: N-(3-Chloro-4-methoxy-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-acetamide

[0637] Intermediate 76B was prepared from Intermediate 76A using Method XIV. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 1.74 (6H, s, CH₃), 3.89 and 3.90 (3H, 2 s, OCH₃), 4.40, 4.46, 4.51 and 4.58 (4H, 4 s, 2 ×NCH₂), 6.15 and 6.16 (1H, 2 s, CH), 6.84-7.27 (7H, m, aromatics). HRMS (ESI⁺) calculated for C₂₂H₂₂ClFNO₅ [M+H⁺] calculated for: 434.11707: found: 434.11820.

[0638] Compound 76: 3-[(3-Chloro-4-methoxy-benzyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0639] Compound 76 was prepared from Intermediate 76B using Method XVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 3.90 and 3.91 (3H, 2 s, OCH₃), 4.41, 4.47, 4.53 and 4.59 (4H, 4 s, 2×NCH₂), 6.39 (1H, broad s, CH), 6.87-7.25 (7H, m, aromatics). HRMS (MAB N₂) calculated for C₁₉H₁₇ClFNO₅ [M⁺]: 393.07794: found: 393.07000.

EXAMPLE 77

[0640] Intermediate 77A: (4-Fluorophenyl)-(3-pyridyl)-methanol

[0641] A solution of 3-pyridinecarboxaldehyde (5.32 g, 49.7 mmol) in tetrahydrofuran (100 ml) was cooled to-78° C. and treated dropwise with 25 ml (50 mmol) of a 2 M solution of 4-fluorophenyl magnesium bromide in ether. The reaction mixture was then slowly warmed up to 0° C. over 1 h and then quenched by the addition of saturated aqueous sodium bicarbonate and ethyl acetate. The organic phase was washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. Filtration of the residue on a short silica gel pad (elution ethyl acetate) followed by distillation in vacuo gave 9.42 g (93%) of the title material as a clear oil which crystallized upon stamiding. bp 120-130° C./0.2 torr (bulb to bulb distillation, air bath temperature), mp 45-47° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 5.88 (1H, s, CH benzhydryl), 7.05 (2H, m, aromatics), 7.25-7.36 (3H, m, aromatics), 7.73 (1H, d, J=7.9 Hz, aromatic), 8.44 (1H, d, J=5.2 Hz, aromatic), 8.55 (1H, s, aromatic). Anal. Calcd for C₁₂H₁₀FNO: C 70.92, H 4.96, N 6.89. Found: C 70.61, H 4.86, N6.71.

[0642] Intermediate 77B: (4-Fluorophenyl)-(3-pyridyl)-N-methyl-methylamine

[0643] A solution of Intermediate 77A (2.0 g, 9.84 mmol) in dry benzene was treated with thionyl chloride (1.7 ml) and heated under reflux for 1 h. The solvent and excess reagent were evaporated under reduce pressure. The residue was then dissolved in 60 ml of a 1.85 M solution of methylamine in tetrahydrofuran and the resulting mixture was heated at 125° C. in a pressure vessel for 72 h. The reaction mixture was then diluted with ethyl acetate, washed with water, brine and dried (magnesium sulfate). Evaporation of the solvent under reduce pressure and filtration of the residue on a short silica gel pad (elution ethyl acetate-methanol 0-20%) followed by distillation in vacuo gave 1.38 g (64%) of the title amine as a clear oil: bp 90-100° C./0.2 torr (bulb to bulb distillation, air bath temperature). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.33 (3H, s, CH₃), 4.65 (1H, s, CH benzhydryl), 6.93 (2H, m, aromatics), 7.16 (1H, dd, J=4.8 Hz and J=7.8 Hz, aromatic), 7.29 (2H, m, aromatics), 7.61 (1H, m, aromatic), 8.41 (1H. broad d, aromatic), 8.56 (1H, d, J=2.1 Hz, aromatic). Anal. Calcd for C₁₂H₁₀FNO. 0.2H₂O: C 71.02, H 6.14, N12.74. Found: C 71.19; H 5.98; N12.75.

[0644] Intermediate 77B: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-[(4-fluoro-phenyl)-pyridin-3-yl-methyl]-N-methyl-acetamide

[0645] Intermediate 77C was prepared from Intermediate 77B using Method XIV. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 1.56, 1.59 and 1.69 (6H, 3 s, CH₃), 2.71 and 2.84 (3H, 2 s, NCH₃), 6.08 and 6.14 (1H, 2 s, CH), 6.93-7.45 and 8.4-8.55 (8H, m, CH and aromatic). HRMS (MAB N₂) calculated for C₂₀H₁₉FN₂O₄ [M⁺]: 370.13288: found: 370.13248.

[0646] Compound 77: 3-{[(4-Fluoro-phenyl)-pyridin-3-yl-methyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0647] Compound 77 was prepared from Intermediate 77B using Method XVIII. ¹HNMR 400 MHz (DMSO-d₆) δ (ppm) mixture of rotamers of keto (minor)-enol forms; 2.72 and 2.88 (3H, 2 s, NCH₃), 6.28 and 6.43 (1H, 2 s, CH), 6.94 and 6.99 (1H, 2 s, CH), 7.25 (4H, m, aromatics), 7.42 (1H, m, aromatic), 7.60 (1H, m aromatic), 8.41 (1H, broad s, aromatic), and 8.55 (1H, m, aromatic). HRMS (MAB N₂₎ calculated for C₂₇H₁₅FN₂O₄ [M^(+]): 330.10158: found: 330.10009.

EXAMPLE 78

[0648] Intermediate 78A: 1,2-Bis-(4-fluorophenyl)-N-methyl-ethylamine

[0649] Intermediate 78A was prepared from 4,4′-difluro-deoxybenzoin using Method III. Anal. Calcd for C₁₅H₁₅F₂N: C 72.86, H 6.11, N 5.66. Found: C 72.48, H 6.27, N 5.75. The hydrochloride salt was obtained as a white solid; mp 155-157° C. ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 2.39 (3H, broad s, NCH₃), 3.14 (1H, dd, J -11.0 Hz and J=13.2 Hz. CH), 3.51 (1H, dd, J=4.58 Hz and J=13.2 Hz. CH), 4.49 (1H, broad. CH), 7.03 (4H, m, aromatics), 7.22 (2H, m, aromatics), 7.50 (2H, m, aromatics).

[0650] Intermediate 78B: N-[1,2-Bis-(4-fluoro-phenyl)-ethyl]-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0651] Intermediate 78B was prepared from Intermediate 78A using Method XIV. MS (ESI⁺) (m/z): 402 (M+H)⁺

[0652] Compound 78: 3-{[1,2-Bis-(4-fluoro-phenyl)-ethyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0653] Compound 78 was prepared from Intermediate 78B using Method XVIII. MS(ESI⁻) (m/z): 360 (M−H).

EXAMPLE 79

[0654] Intermediate 79A: 4-Fluoro-3′-(N-methylcarbamoyl)-benzophenone

[0655] A solution of 3-{1-hydroxy-1-(4-fluorophenyl)-methyl}-N-methyl-benzamide (0.91 g, 3.51 mmol) in dichloromethane (75 ml) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane) (5.9 g, 13.9 mmol) and the resulting mixture was stirred at 25° C. for 18 h. The solution was then diluted with ethyl acetate, washed with 5% aqueus sodium thiosulfate, sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent under reduce pressure and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 1: 1) gave 0.854 g (94%) of the title material as a white solid: mp 118-119° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.05 (3H, d, J=4.7 Hz, NCH₃), 6.29 (1H, broad, NH), 7.20 (2H, m, aromatics), 7.59 (1H, t, J=8.0 Hz, aromatic), 7.84-7.3 (3H, m, aromatics), 8.05 (1H, m, aromatic), 8.14 (1H broad s, aromatic). Anal. Calcd for C₁₅H₁₂FNO₂: C 70.03, H 4.70, N 5.44. Found: C 70.04, H 4.59, N 5.36.

[0656] Intermediate 79B: 4-Fluoro-3′-(N-methylcarbamoyl)-benzhydrylmethylamine

[0657] Intermediate 79B was prepared using Method III from Intermediate 79A. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.36 (3H, s, NCH₃), 2.95 and 2.97 (3H, 2 s, NCH₃), 4.7 (1H, s. CH), 6.38 (1H, broad, NH), 6.95 (2H, m, aromatics), 7.32 (3H, m, aromatics), 7.47 (1H, broad d, aromatic), 7.60 (1H, broad d, aromatic), 7.79 (1H, broad s, aromatic). MS (ESI⁺) (m/z): 273 (M+H).

[0658] Intermediate 79C: 3-[{[2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl]-methyl-amino}-(4-fluoro-phenyl)-methyl]-N-methyl-benzamide

[0659] Intermediate 79C was prepared from Intermediate 79B using Method XIV. ¹HNMR 400 MHz (DMSO-d₆) 6 (ppm): mixture of rotamers; 1.48, 1.52 and 1.69 (6H, 3 s, CH₃), 2.63 and 2.82 (3H, 2 s, NCH₃), 2.76 (2H, d, J=4.56 Hz, CH₃), 6.19 (1H, broad s, CH benzhydryl), 6.58 and 6.96 (1H, 2 s, CH), 7.21 (4H, m, aromatics), 7.27 (1H, d, J=8.2 Hz, aromatic), 7.47 (1H, t, J=7.9 Hz, aromatic), 7.64 (1H, broad s, aromatic), 7.79 (1H, d, J=8.0 Hz, aromatic) and 8.49 (1H, s, NH). HRMS (ESI⁺) calculated for C₂₃H₂₄FN₂O₅ [M+H⁺]: 427.16693: found: 427.16840.

[0660] Compound 79: 3-{[(4-Fluoro-phenyl)-(3-methylcarbamoyl-phenyl)-methyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0661] Compound 79 was prepared from Intermediate 79C using Method XVIII. ¹HNMR 400 MHz (DMSO-d₆) 6 (ppm): mixture of rotamers; 2.70 and 2.87 (3H, 2 s, NCH₃), 2.76 (2H, d, J=4.5 Hz, NCH₃), 6.31 and 6.41 (1H, 2 s, CH benzhydryl), 6.76 and 6.99 (1H, 2 s, CH), 7.21 (4H, m, aromatics), 7.19-7.81 (8H, m, aromatics). HRMS (MAB N₂) calculated for C₂₀H₁₉FN₂O₅ [M⁺]: 386.12780: found: 386.12843.

EXAMPLE 80

[0662] Intermediate 80A: 3,3-bis-(4-fluorophenyl)-propionic Acid Ethyl Ester

[0663] A suspension of zinc (5.7 g, 87.2 mmol) in dichloromethane (20 ml) was treated with iodine (0.1 g) and heated under reflux. A solution of ethyl bromoacetate (10.0 g, 59.8 mmol) in dichloromethane was then added dropwise over 15 min and the resulting mixture was heated for another 15 min. The thick paste was then cooled to 0-5° C. and treated dropwise with a solution of 4,4′-difluorobenzhydryl chloride (11.93 g, 50.0 mmol) in dichloromethane (20 ml). The cooling bath was then removed and the mixture was stirred at 22° C. for another 2 h. The reaction mixture was quenched by the addition of 1N hydrochloric acid and ethyl acetate. The organic phase was washed with water, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent under reduce pressure and distillation of the residue in vacuo gave 11.6 g (80%) of the title material as a clear oil: bp 95-100° C./0.1 torr (bulb to bulb distillation, air bath temperature). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.14 (3H, t, J=7.1 Hz, CH₃), 3.01 (2H, d, J=8.1 Hz, CH₂), 4.06 (2H, q, J=7.1 Hz, CH₂), 4.54 (1H, t, J=8.1 Hz, CH),7.0 (4H, m, aromatics), 7.2 (4H, m, aromatics). Anal. Calcd for C₁₇H₁₆F₂O₂: C 70.34, H 5.56. Found: C 70.44, H 5.50.

[0664] Intermediate 80B: 3,3-bis-(4-fluorophenyl)-propionic Acid

[0665] Saponification of Intermediate 80A as described in the preparation of Intermediate 1B gave the title acid as white needles: mp 106-107° C. (benzene-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 3.05 (2H, d, J=8.1 Hz, CH₂), 4.51 (1H, t, J=8.1 Hz, CH), 7.0 (4H, m, aromatics), 7.18 (4H, m, aromatics). Anal. Calcd for C₁₅H₁₂F₂O₂: C 68.69, H 4.61. Found: C 68.71, H 4.63.

[0666] Intermediate 80C: 3,3-bis-(4-Fluorophenyl)-N-methyl-propylamine

[0667] Intermediate 80C was prepared from Intermediate 80B using Method II. ¹HNMR 400 MHz (CDCl₃) δ (ppm: 2.18 (2H, m, CH₂), 2.39 (3H, s, NCH₃), 2.51 (2H, t, J=7.3 Hz, CH₂), 3.99 (1H, t, J=8.0 Hz, CH), 6.96 (4H, m, aromatics), 7.16 (4H, m, aromatics). MS (ESI⁺) (m/z): 262 (M+H).

[0668] Intermediate 80D: N-[3,3-Bis-(4-fluoro-phenyl)-propyl]-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0669] Intermediate 80D was prepared from Intermediate 80C using Method XIV. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 1.67 and 1.72 (6H, 2 s, CH₃), 2.29 (2H, m, CH₂), 2.97 and 3.01 (3H, 2 s, NCH₃), 3.27 and 3.35 (2H, 2 m, NCH₂), 3.87 and 3.92 (1H, 2 t, J=7.98 and J=7.83 Hz, CH), 5.85 and 6.07 (1H, 2 s, CH), 6.98 (4H, m, aromatics) and 7.17 (4H, m, aromatics). HRMS (ESI⁺) calculated for C₂₃H₂₄F₂NO₄ [M+H⁺]: 416.16733: found: 416.16850.

[0670] Compound 80: 3-{[3,3-Bis-(4-fluoro-phenyl)-propyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0671] Compound 80 was prepared from Intermediate 80D using Method XVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm) mixture of rotamers; 2.29 (2H, m, CH₂), 3.0 (3H, s, NCH₃), 3.29 and 3.39 (2H, 2 m, NCH₂), 3.88 and 3.91 (1H, 2 t, J 7.7 and J=8.2 Hz, CH), 6.01 and 6.24 (1H, 2 s, CH), 7.08 (4H, m, aromatics) and 7.19 (4H, m, aromatics). HRMS (MAB N₂) calculated for C₂₀H₁₉F₂NO₄ [M⁺]: 375.12821: found: 375.12874.

EXAMPLE 81

[0672] Intermediate 81A: 2-{1-Hydroxy-1-(4-fluorophenyl)-methyl}-N-methyl-benzamide

[0673] Reaction of 2-bromo-N-methylbenzamide with 4-fluorobenzaldehyde as described in the preparation of Intermediate 2A gave the title material as a white solid: mp: 133-134° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm) 2.81 (3H, d, J=5.1 Hz, NCH₃), 5.89 (2H, broad s, CH and NH), 7.01 (2H, m, aromatics), 7.28-7.45 (6H, m, aromatics). Anal. Calcd for C₁₅H₁₄FNO₂: C 69.49, H 5.44, N 5.40. Found: C 69.46, H 5.44, N 5.41.

[0674] Intermediate 81B: 2-(4-Fluorobenzyl)-N-methyl-benzamide

[0675] Hydrogenolysis of Intermediate 81A, as described in the preparation of Intermediate 2B, gave the title amide as white needles: mp 129-130° C. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 2.9 (3H, d, J=4.5 Hz, NCH₃), 4.16 (2H, s, CH₂), 5.61 (1H, broad, NH), 6.96 (2H, m, aromatics), 6.99-7.38 (6H, m, aromatics). Anal. Calcd for C₁₅H₁₄FNO: C 74.06, H 5.80, N5.76. Found: C 74.08, H 5.86, N 5.69.

[0676] Intermediate 81D: 2-(4-Fluorobenzyl)-N-methyl-benzylamine

[0677] Reduction of Intermediate 81C, as described in the preparation of Intermediate 8B, gave the title amine as an oil: bp 85-90° C./0.1 torr (bulb to bulb distillation, air bath temperature). ¹HNMR 400 MHz (C₆D₆) 6 (ppm): 2.26 (3H, s, NCH₃), 3.54 (2H, s, CH₂), 4.0 (2H, s, CH₂), 6.87 (2H, m, aromatics), 6.94 (2H, m, aromatics), 7.07 (1H, d, aromatic), 7.23 (2H,m aromatics),7.4 (1H, d, aromatic). MS (ESI⁺) (m/z): 230 (M+H). Anal. Calcd for C₁₅H₁₆FN: C 78.57, H 7.03, N 6.10. Found: C 78.37; H 7.00; N 6.16.

[0678] Intermediate 81E: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-[2-(4-fluoro-benzyl)-benzyl]-N-methyl-acetamide

[0679] Intermediate 81E was prepared from Intermediate 81D using Method XIV. ¹HNMR 400 MHz (CDCl₃) δ (ppm: mixture of rotamers; 1.59 and 1.72 (6H, 2 s, CH₃), 2.81 and 2.92 (3H, 2 s, NCH₃), 3.96 and 3.99 (2H, 2 s, CH₂), 4.43 and 4.64 (2H, 2 s, NCH₂), 5.88 and 6.03 (H, 2 s, CH), 6.91-7.3 (8H, m, aromatics). HRMS (MAB N₂₎ calculated for C₂₂H₂₂FNO₄ [M^(+]): 383.15329: found: 383.15425.

[0680] Compound 81: 3-{[2-(4-Fluoro-benzyl)-benzyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0681] Compound 81 was prepared from Intermediate 81E using Method XVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 2.80 and 2.94 (3H, 2 s, NCH₃), 3.98 and 3.99 (2H, 2 s, CH₂), 4.44 and 4.64 (2H, 2 s, NCH₂), 6.06 and 6.19 (H, 2 s, CH), 6.90-7.36 (8H, m, aromatics). HRMS (MAB N₂) calculated for C₁₉H₁₈FNO4 [M⁺]: 343.12199: found: 343.12171.

EXAMPLE 82

[0682] Intermediate 82A: 2-(4-Fluorobenzyloxy)-N-methyl-benzylamine

[0683] Intermediate 82A was prepared from 2-(4-fluorobenzyloxy)-benzaldehyde (Hellwinkle et al using Method III. Synthesis 1995, 1135.). ¹HNMR 400 MHz (C₆D₆) δ (ppm): 1.90 (3H, s, NCH₃), 3.56 (2H, s, NCH₂), 4.77 (2H, s, OCH₂), 6.50 (1H, d, J=7.6 Hz, aromatic), 6.73 (1H, broad t, aromatic), 6.83 (2H, m, aromatics), 6.95 (1H, broad t, aromatic), 7.28 (2H, m, aromatics), 7.47 (1H, d, J=7.7 Hz, aromatic). HRMS (MAB N₂) calculated for C₁₅H₁₆FNO [M^(+]): 245.12159: found: 245.12192, δ-1.3 ppm.

[0684] Intermediate 82B: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-[2-(4-fluoro-benzyloxy)-benzyl]-N-methyl-acetamide

[0685] Intermediate 82B was prepared from Intermediate 82A using Method XIV. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 1.67 and 1.73 (6H, 2 s, CH₃), 2.98 and 3.01 (3H, 2 s, NCH₃), 4.57 and 4.72 (2H, 2 s, NCH₂), 5.04 (2H, s, OCH₂), 6.1 and 6.16 (H, 2 s, CH), 6.91-7.41 (8H, m, aromatics). HRMS (MAB N₂) calculated for C₂₂H₂₂FNO₅ [M^(+]): 399.1482: found: 399.1499.

[0686] Compound 82: 3-{[2-(4-Fluoro-benzyloxy)-benzyl]-methyl-carbamoyl}-2-hydroxy-acrylic Acid

[0687] Compound 82 was prepared from Intermediate 82B using Method XVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 3.0 and 3.01 (3H, 2 s, NCH₃), 4.58 and 4.72 (2H, 2 s, NCH₂), 5.03 (2H, s, OCH₂), 6.30 and 6.32 (H, 2 s, CH), 6.95-7.52 (8H, m, aromatics). HRMS (MAB N₂₎ calculated for C₁₉H₁₈FNO₅ [M^(+]): 359.1169: found: 359.1165.

EXAMPLE 83

[0688] Intermediate 83A: (4-chlorobenzyl)-(3,4-dichlorobenzyl)-amine

[0689] Intermediate 83A was prepared from N-(4-chlorobenzyl)-3,4-dichlorobenzamide (Borgma et al. Farmaco Ed. Sci. 1977, 32, 813) using Method II, step 2. ¹HNMR 400 MHz (C₆D₆) δ (ppm): 3.22 (2H, s, NCH₂), 3.31 (2H, s, NCH₂), 6.78 (1H, d, J=8.5 Hz, aromatic), 6.99 (2H, d, J=8.1 Hz, aromatics), 7.15 (2H, d, J=8.1 Hz, aromatics), 7.24-7.31 (3H, m, aromatics).

[0690] Intermediate 83B: N-(4-Chloro-benzyl) —N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1, 3]dioxolan-4-ylidene)-acetamide

[0691] Intermediate 83B was prepared from Intermediate 83A using Method XIV. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 1.77 (6H, s, CH₃), 4.47, 4.51, 4.57 and 4.6 (4H, 4 s, 2×NCH₂), 6.12 and 6.17 (1H, 2 s, CH), 7.02-7.47 (7H, m, aromatics). HRMS (FAB) calculated for C₂₁H₁₉Cl₃NO₄ [M+H⁺]: 454.03796 found: 454.03740.

[0692] Compound 83: 3-[(4-Chloro-benzyl)-(3,4-dichloro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0693] Compound 83 was prepared from Intermediate 83B using Method XVIII. Solid: mp 152° C. (dec. (hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 4.48, 4.51, 4.59 and 4.63 (4H, 4 s, 2×NCH₂), 6.35 and 6.41 (1H, 2 s, CH), 7.08-7.48 (7H, m, aromatics). HRMS (FAB) calculated for C₁₈H₁₅Cl₃NO₄ [M+H⁺]: 414.00665: found: 414.00820.

EXAMPLE 84

[0694] Intermediate 84A: 2-Benzyl-N-methyl-benzylamine

[0695] Intermediate 84A was prepared using Method II, step 2 from Intermediate 81B. ¹HNMR 400 MHz (C₆D₆) δ (ppm): 2.27 (3H, s, NCH₃), 3.6 (2H, s, CH₂), 4.13 (2H, s, CH₂), 7.14-7.45 (8H, m, aromatics). MS (ESI⁺) (m/z): 212 (M+H). Hydrochloride salt: Anal. Calcd for C₁₅H₁₆FN. HCl: C, 72.72; H, 7.32; N5.65. Found: C 72.71, H 7.26, N 5.64.

[0696] Intermediate 84B: N-(2-Benzyl-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide

[0697] Intermediate 84B was prepared from Intermediate 84A using Method XIV. ¹HNMR 400 MHz (CDCl₃) δ (ppm) mixture of rotamers; 1.67 and 1.74 (6H, 2 s, CH₃), 2.78 and 2.93 (3H, 2 s, NCH₃), 4.03 and 4.06 (2H, 2 s, CH₂), 4.47 and 4.69 (2H, 2 s, NCH₂), 5.93 and 5.99 (H, 2 s, CH), 7.09-7.34 (8H, m, aromatics). MS (ESI⁺) (m/z) 366 (M+H⁺)

[0698] Compound 84: 3-[(2-Benzyl-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0699] Compound 84 was prepared from Intermediate 84B using Method XVIII. ¹HNMR 400 MHz (CDCl₃) δ (ppm) mixture of rotamers; 2.78 and 2.94 (3H, 2 s, NCH₃), 4.05 and 4.06 (2H, 2 s, CH₂), 4.48 and 4.68 (2H, 2 s, NCH₂), 6.11 and 6.18 (H, 2 s, CH), 7.04-7.37 (8H, m, aromatics). HRMS (MAB N₂) calculated for C₁₉H₁₉NO₄ [M⁺]: 325.131408: found: 325.130098.

EXAMPLE 85

[0700] Intermediate 85A: N-(3-Biphenyl-4-yl-propyl)-N-(4-fluoro-benzyl)-acetamide

[0701] Intermediate 85A was prepared from (3-biphenyl-4-ylpropyl)-(4-fluorobenzyl)-amine hydrochloride using Method IV. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (CDCl₃) δ: 1.90 (m), 2.10 (s), 2.11 (s), 2.65 (m), 3.21 (m), 3.42 (m), 4.46 (s), 4.54 (s), 6.95-7.60 (overlapping m).

[0702] Compound 85: 3-[(3-Biphenyl-4-yl-propyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0703] Compound 85 was prepared from Intermediate 85A using Method XII. MS (M−H) calcd for C₂₆H₂₃NO₄F: 432.16; found: 432.11. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.99 (m), 2.66 (m), 3.26 (m), 3.47 (m), 3.76 (m), 4.48 (s), 4.57 (s), 6.30 (s), 6.33 (s), 6.96-7.61 (overlapping m).

EXAMPLE 86

[0704] Intermediate 86A: N-(4-Fluoro-benzyl)-N-(2-pyridin-4-yl-ethyl)-acetamide

[0705] Intermediate 86A was prepared from N-(2-pyridin-4-yl-ethyl)-acetamide and 4-fluorobenzylbromide using Method VII. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, d₆-MeOD) δ: 2.03 (s), 2.12 (s), 2.87 (t, J=8), 2.93 (t, J=8), 3.59 (m), 4.56 (s), 4.60 (s), 7.06 (m), 7.23-7.31 (overlapping m), 8.40 (m), 8.44 (m).

[0706] Compound 86: 3-[(4-Fluoro-benzyl)-(2-pyridin-4-yl-ethyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0707] Compound 86 was prepared from Intermediate 86A using Method XII. MS (M−H calcd for C₁₈H₁₆N₂O₄F: 343.11; found:343.06. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, d₆-MeOD) δ: 3.19 (m), 3.83 (m), 4.71 (s), 6.08 (s), 6.30 (s), 7.05 (m), 7.29 (m), 7.35 (m), 7.95 (m), 8.72 (m).

EXAMPLE 87

[0708] Intermediate 87A: N-[3-(2-Chloro-phenyl)-propyl]-N-(4-fluoro-benzyl)-acetamide

[0709] Intermediate 87A was prepared from [3-(2-chloro-phenyl)-propyl]-(4-fluoro-benzyl)-amine hydrochloride using Method IV. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.86 (m), 2.12 (s), 2.70 (m), 3.23 (m), 3.42 (m), 4.48 (s), 4.54 (s), 6.95-7.36 (overlapping m).

[0710] Compound 87: 3-[[3-(2-Chloro-phenyl)-propyl]-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0711] Compound 87 was prepared from Intermediate 87A using Method XII. MS (M−H) calcd for C₂₀H₁₈NO₄ClF: 390.04; found: 390.07. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (300 MHz, d₆-MeOD) δ: 1.87 (m), 2.72 (m), 3.36 (m), 3.50 (m), 4.63 (s), 6.25 (s), 6.31 (s), 6.92-7.36 (overlapping m).

EXAMPLE 88

[0712] Intermediate 88A: N-(4-Fluoro-benzyl)-N-[2-(4-fluoro-benzyloxy)-phenyl]-acetamide

[0713] Intermediate 88A was prepared from 2-(4-fluoro-benzyloxy)-phenylamine and 4-fluorobenzylbromide the same method used for Intermediate 43A. ¹H NMR (500 MHz, CDCl₃) δ: 1.83 (s, 3), 4.46 (d, 1, J=14), 4.90 (dd, 2, J=12, 60), 5.01 (d, 1, J=14). 6.59-7.25 (overlapping m, 12).

[0714] Intermediate 88B: 3-{(4-Fluoro-benzyl)-[2-(4-fluoro-benzyloxy)-phenyl]-carbamoyl}-2-hydroxy-acrylic Acid Methyl Ester

[0715] Intermediate 88B was prepared from intermediate 88A using Method IX. MS (M−H) calcd for C₂₅H₁₉F₃NO₅: 470.1; found: 470.1 ¹H NMR (500 MHz, CDCl₃) δ: 3.80 (s, 3), 4.48 (d, 1, J=14), 4.93 (dd, 2, J=12, 33), 5.12 (d, 1, J=14), 5.64 (s, 1), 6.60-7.22 (overlapping m, 12).

[0716] Compound 88: 3-{(4-Fluoro-benzyl)-[4-fluoro-2-(4-fluoro-benzyloxy)-phenyl]-carbamoyl}-2-hydroxy-acrylic acid

[0717] Compound 88 was prepared from Intermediate 88B using Method XII. MS (M−H) calcd for C₂₄H₁₇NO₄F₃: 456.11; found: 456.00. ¹H NMR (500 MHz, CDCl₃) δ: 4.50 (d, J=14), 4.89 (d, J=12), 4.95 (d, J=12), 5.09 (d, J=14), 5.73 (s), 6.61-7.21 (m).

EXAMPLE 89

[0718] Intermediate 89A: N-(3,5-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)N-methylacetamide

[0719] Coupling of (Z)-2,2-dimethyl-5-(carboxymethylene)-1,3-dioxolan-4-one with N-methyl-3,5-dichlorobenzylamine (Meindl, W. R. et al., J. Med. Chem., 27, 1984, 1111-1118) as described in Method XIV gave the title material as a syrup. ¹HNMR 400 MHz (CDCl₃) δ (ppm): mixture of rotamers; 1.71 and 1.75 (6H, 2 s, CH₃)₁ 2.98 and 3.04 (3H, 2 s, NCH₃), 4.54 and 4.60 (2H, 2 s, NCH₂), 6.08 and 6.18 (1H, 2 s, CH), 7.07-7.31 (3H, m, aromatics). HRMS (MAB N₂) calculated for C₁₅H₁₅Cl₂NO₄ [M⁺]: 343.037814: found: 343.038563.

[0720] Compound 89: 3-[(3,5-dichloro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic Acid

[0721] Saponification of Intermediate 89A carried out using Method XVIII yielded the title acid as a white solid. ¹HNMR 400 MHz (DMSO-d₆) 6 (ppm): mixture of rotamers; 3.06 (3H, s, NCH₃), 4.55 and 4.61 (2H, 2 s, NCH₂), 6.31 and 6.39 (1H, 2 s, CH), 7.05-7.34 (3H, m, aromatics). HRMS (MAB N₂) calculated for C₁₂H₁₁Cl₂NO₄ [M⁺]: 303.006513: found: 303.007587.

EXAMPLE 90

[0722] Intermediate 90A: N-(3,4-Dichlorophenyl)-4-fluorobenzamide

[0723] Reaction of 4-fluorobenzoyl chloride with 3,4-dichloroaniline using Method II, step 1, gave the title amide as crystals: mp 160-161° C. (ethyl acetate-hexane). ¹HNMR 400 MHz (CDCl₃) δ (ppm): 7.19 (2H, m, aromatics), 7.44 (2H, m, aromatics), 7.70 (1H, broad, NH), 7.88 (3H, m, aromatics). Anal. Calcd for C₁₃H₁₈Cl₂FNO: C 54.96; H 2.84; N 4.93. Found: C 54.96; H 2.87; N 4.90.

[0724] Intermediate 90B: (3,4-Dichlorophenyl)-(4-fluorobenzyl)-amine

[0725] Reduction of Intermediate 90A using Method II step 2, gave the title amine. The hydrochloride salt was obtained as a white solid. ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 4.25 (2H, s, NCH₂), 6.56 (1H, dd, J=2.6 Hz and J=8.7 Hz, aromatic), 6.73 (1H, d, J=2.6 Hz, aromatic), 7.15 (2H, m, aromatics), 7.22 (1H, d, J=8.7 Hz, aromatic), 7.36 (2H, m, aromatics).

[0726] Intermediate 90C: N-(3,4-dichloro-phenyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-acetamide

[0727] Acylation of Intermediate 90B with (Z)-2,2-dimethyl-5-(chlorocarbonylmethylene)-1,3-dioxolan-4-one as described in Method XIV gave the title amide as a foam. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.73 (6H, s, CH₃), 4.88 (2H, s, NCH₂), 5.63 (1H, s, CH), 6.81 (1H, dd, J=2.7 Hz and J=8.5 Hz, aromatic), 6.97 (2H, m, aromatics), 7.15 (1H, d, J=2.7 Hz, aromatic), 7.19 (2H, m, aromatics), 7.41 (1H, d, J=8.5 Hz, aromatic). HRMS (FAB) calculated for C₂₀H₁₇Cl₂FNO₄ [M+H⁺]: 424.05188: found: 424.05120.

[0728] Compound 90: 3-[(3,4-dichloro-phenyl)-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acrylic Acid

[0729] Saponification of Intermediate 90C carried out using Method XVIII yielded the title acid as a white solid. ¹HNMR 400 MHz (DMSO-d₆) 6 (ppm): 4.97 (2H, s, NCH₂), 5.75 (1H, broad s, CH), 7.12 (2H, m, aromatics), 7.2 (1H, dd, aromatic), 7.27 (2H, m, aromatics), 7.69 (1H, d, J=8.6 Hz, aromatic), 7.71 (1H, d, J=2.4 Hz, aromatic). HRMS (MAB N₂) calculated for C₁₇H₁₂Cl₂FNO₄ [M⁺]: 383.012742: found: 383.012742.

EXAMPLE 91

[0730] Intermediate 91A: 2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(3-fluoro-4-methyl-benzyl)-acetamide

[0731] Intermediate 91A was prepared 3-fluoro-4-methyl-benzyl-amine hydrochloride using Method XVII HRMS (M+H) calcd for C₁₅H₁₇NO₄F: 294.1142; found: 294.1146. ¹H NMR (500 MHz, CDCl₃) δ: 1.73 (s, 6), 2.25 (s, 3), 4.49 (s, 1), 4.50 (s, 1) 5.90 (s, 1), 6.69 (br s, 1), 6.96 (m, 2), 7.13 (m, 1). ¹³C NMR (125 MHz, CDCl₃) δ: 14.29, 26.86, 29.52, 42.84, 67.10, 101.21, 107.65, 113.97, 114.05, 114.23, 122.90, 122.93, 123.94, 124.07, 131.65, 131.69, 137.77, 143.05, 160.41, 161.66, 162.35, 163.07.

[0732] Compound 91: 3-(3-Fluoro-4-methyl-benzylcarbamoyl)-2-hydroxy-acrylic Acid

[0733] Compound 91 was prepared from Intermediate 91A using Method XVIII. HRMS (M−H) calcd for C₁₂H₁₁NO₄F: 252.0672; found: 252.0676. ¹H NMR (500 MHz, DMSO) δ: 2.20 (s, 3), 4.36 (m, 2), 6.04 (s, 1), 7.03 (m, 2), 7.25 (m, 1), 9.01 (m, 1). ¹³C NMR (125 MHz, DMSO) δ: 13.72, 13.74, 41.17, 97.80, 113.63, 113.81, 122.65, 122.77, 123.01, 131.47, 131.51, 138.31, 138.37, 157.52, 159.50, 161.43, 163.31, 170.32.

EXAMPLE 92

[0734] Intermediate 92A: N-[Bis-(4-chloro-phenyl)-methyl]-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetamide

[0735] Intermediate 92A was prepared from Bis-(4-chloro-phenyl)-methyl-amine hydrochloride using Method XIV. ¹HNMR 400 MHz (CDCl₃) δ (ppm): 1.75, (6H, s, CH₃), 5.93 (1H, s, CH), 6.29 (1H, d, J=8.2 Hz, CH benzhydryl), 6.75 (1H, broad d, NH), 7.18 (4H, broad d, aromatics), 7.34 (4H, broad d, aromatics). HRMS (MAB N₂) calculated for C₂₀H₁₇Cl₂NO₄ [M^(30 ]): 405.05364: found: 405.05432.

[0736] Compound 92: 3-{[Bis-(4-chloro-phenyl)-methyl]-carbamoyl}-2-hydroxy-acrylic Acid

[0737] Compound 92 was prepared from Intermediate 92A using Method XVIII. ¹HNMR 400 MHz (DMSO-d₆) δ (ppm): 6.16 (1H, s, CH), 6.23 (1H, d, J=8.7 Hz, CH benzhydryl), 7.32 (4H, broad d, aromatics), 7.44 (4H, broad d, aromatics), 9.44 (1H, d, J=8.7 Hz, NH). HRMS (MAB N₂₎ calculated for C₁₇H₁₃Cl₂NO₄ [M^(+]): 365.02216: found: 365.02317.

[0738] Chemical intermediates of the present invention, having the following formula, were prepared according to Method XV.

HPLC Retention Intermediate time MS Data Number Q (min) Formula (M + H)⁺ 93A

1.86 C₁₅H₁₇NO₄ 276 94A

1.83 C₁₅H₁₇NO₅ 292 95A

1.88 C₁₅H₁₇NO₄ 276 96A

1.76 C₁₅H₁₇NO₅ 292 97A

1.92 C₁₅H₁₇NO₄ 276 98A

1.81 C₁₄H₁₄FNO₄ 280 99A

1.99 C₁₄H₁₄ClNO₄ 296 100A

1.74 C₁₅H₁₇NO₅ 292 101A

1.93 C₁₅H₁₇NO₄ 276 102A

2.12 C₁₅H₁₄F₃NO₄ 330 103A

1.77 C₁₄H₁₄N₂O₆ 307 104A

1.98 C₁₄H₁₄ClNO₄ 296 105A

2.34 C₁₈H₂₃NO₄ 318 106A

1.91 C₁₅H₁₆FNO₄ 294 107A

2.12 C₁₄H₁₃Cl₂NO₄ 330 108A

1.84 C₁₆H₁₉NO₆ 322 109A

1.91 C₁₄H₁₃F₂NO₄ 298 110A

1.85 C₁₅H₁₇NO₄ 276 111A

1.85 C₁₅H₁₇NO₄ 276 112A

1.86 C₂₀H₁₉NO₄ 338 113A

1.91 C₂₁H₂₁NO₄ 352 114A

1.99 C₁₆H₁₉NO₄ 290 115A

1.88 C₁₈H₂₃NO₄ 318 116A

1.82 C₁₅H₁₅Cl₂NO₄ 344 117A

1.95 C₂₂H₂₃NO₄ 366 118A

1.77 C₁₆H₁₈ClNO₅ 340 119A

1.64 C₁₆H₁₉NO₄ 290 120A

2.09 C₂₃H₂₅NO₄ 380 121A

1.64 C₁₆H₁₉NO₄ 290 122A

2.18 C₂₄H₂₅Cl₂NO₄ 462 123A

2.01 C₂₂H₂₂FNO₄ 384 124A

1.95 C₂₀H₂₇NO₅ 362 125A

2.06 C₂₃H₂₄ClNO₅ 430 126A

1.53 C₂₁H₂₈NO₂O₇ 421 127A

2.71 C₂₄H₂₇NO₅ 410 128A

2.29 C₂₄H₂₇NO₆ 426 129A

1.95 C₁₆H₁₉NO₄ 290 130A

2.53 C₂₁H₃₀N₂O₄ 375 131A

1.47 C₁₅H₁₈N₂O₄ 291 132A

1.71 C₁₈H₂₃NO₆ 350 133A

2.39 C₂₃H₂₇NO₆ 414 134A

2.15 C₁₈H₂₃NO₅ 334 135A

2.46 C₂₂H₂₉NO₆ 404 136A

2.62 C₂₆H₂₇NO₄ 418 137A

2.36 C₁₈H₂₃NO₄ 318 138A

2.15 C₂₀H₂₆N₂O₅ 375 139A

2.22 C₁₉H₁₉NO₄ 326 140A

1.74 C₁₉H₂₅NO₆ 364 141A

2.63 C₂₅H₂₈N₂O₄ 421 142A

2.89 C₃₀H₃₁NO₄ 470 143A

3.9 C₂₆H₃₀FNO₄ 440

[0739] Compounds of the present invention, as shown in the following formula, were prepared according to Method XIX.

Compound MS Data Number Q Formula (M − H)⁻ 93

C₁₂H₁₃NO₄ 234 94

C₁₂H₁₃NO₅ 250 95

C₁₂H₁₃NO₄ 234 96

C₁₂H₁₃NO₅ 250 97

C₁₂H₁₃NO₄ 234 98

C₁₁H₁₀FNO₄ 238 99

C₁₁H₁₀ClNO₄ 254 100

C₁₂H₁₃NO₅ 250 101

C₁₂H₁₃NO₄ 234 102

C₁₂H₁₀F₃NO₄ 288 103

C₁₁H₁₀N₂O₆ 265 104

C₁₁H₁₀ClNO₄ 254 105

C₁₅H₁₉NO₄ 276 106

C₁₂H₁₂FNO₄ 252 107

C₁₁H₉Cl₂NO₄ 288 108

C₁₃H₁₅NO₆ 280 109

C₁₁H₉F₂NO₄ 256 110

C₁₂H₁₃NO₄ 234 111

C₁₂H₁₃NO₄ 234 112

C₁₇H₁₅NO₄ 296 113

C₁₈H₁₇NO₄ 310 114

C₁₃H₁₅NO₄ 248 115

C₁₅H₁₉NO₄ 276 116

C₁₂H₁₁Cl₂NO₄ 302 117

C₁₉H₁₉NO₄ 324 118

C₁₃H₁₄ClNO₅ 298 119

C₁₃H₁₅NO₄ 248 120

C₂₀H₂₁NO₄ 338 121

C₁₃H₁₅NO₄ 248 122

C₂₁H₂₁Cl₂NO₄ 420 123

C₁₉H₁₈FNO₄ 342 124

C₁₇H₂₃NO₅ 320 125

C₂₀H₂₀ClNO₅ 388 126

C₁₈H₂₄N₂O₇ 379 127

C₂₁H₂₃NO₅ 368 128

C₂₁H₂₃NO₆ 384 129

C₁₃H₁₅NO₄ 248 130

C₁₈H₂₆N₂O₄ 333 131

C₁₂H₁₄N₂O₄ 249 132

C₁₅H₁₉NO₆ 308 133

C₂₀H₂₃NO₆ 372 134

C₁₅H₁₉NO₅ 292 135

C₁₉H₂₅NO₆ 362 136

C₂₃H₂₃NO₄ 376 137

C₁₅H₁₉NO₄ 276 138

C₁₇H₂₂N₂O₅ 333 139

C₁₆H₁₅NO₄ 284 140

C₁₆H₂₁NO₆ 322 141

C₂₂H₂₄N₂O₄ 379 142

C₂₇H₂₇NO₄ 428 143

C₂₃H₂₆NO₄ 398

EXAMPLE 144

[0740] 5 Compound 144: 2-Hydroxy-but-2-enedioic acid 4-[bis-(4-fluoro-benzyl)-amide] 1-propylamide

[0741] Compound 144 was prepared from Compound 11 using Method XX. MS (M−H) calcd for C₂₁H₂₁N₂O₃F₂: 387.15; found: 387.11. ¹H NMR (500 MHz, d₆-MeOD) δ: 0.92 (t, 3, J=7), 1.58 (sextet, 2, J=7), 3.24 (q, 2, J=7), 4.59 (s, 2), 4.63 (s, 2), 6.32 (s, 1), 7.05 (m, 4), 7.20 (m, 2), 7.28 (m, 2).

EXAMPLE 145

[0742] Compound 145: {3-[Bis-(4-fluoro-benzyl)-carbamoyl]-2-hydroxy-acryloylamino}-acetic Acid

[0743] Compound 145 was prepared from Compound 11 using Method XX. MS (M−H) calcd for C₂₀H₁₇N₂O₅F₂: 403.11; found: 403.12. ¹H NMR (500 MHz, d₆-MeOD) δ: 4.00 (s, 2), 4.60 (s, 20, 4.64 (s, 2), 6.36 (s, 1), 7.05 (m, 4), 7.20 (m, 2), 7.29 (m, 2).

EXAMPLE 146

[0744] Compound 146: 2-Hydroxy-but-2-enedioic acid 1-[(6-benzenesulfonylamino-6-oxo-hexyl)-amide] 4-[bis-(4-fluoro-benzyl)-amide]

[0745] Compound 146 was prepared from Compound 11 using Method XX. MS (M−H) calcd for C₃₀H₃₀N₃O₆SF₂: 598.18; found: 598.05. ¹H NMR (500 MHz, DMSO) δ: 1.07 (m, 2), 1.36 (m, 4), 2.18 (t, 2, J=7), 3.06 (m,2), 4.62 (s, 2), 4.66 (s, 2), 6.15 (s), 7.12-8.506 (overlapping m).

EXAMPLE 147

[0746] Compound 147: 2-Hydroxy-but-2-enedioic acid 1-[(6-benzenesulfonylamino-6-oxo-hexyl)-amide] 4-[[3-(2-chloro-phenyl)-propyl]-(4-fluoro-benzyl)-amide]

[0747] Compound 147 was prepared from Compound 87 using Method XX. MS (M−H) calcd for C₃₂H₃₄N₃O₆SClF: 642.18; found: 642.08. ¹H NMR shows a mixture of rotamers at room temperature. ¹H NMR (500 MHz, CDCl₃) δ: 1.27 (m), 1.50 (m), 1.61 (m), 1.89 (m), 2.27 (m), 2.72 (m), 3.26-3.46 (overlapping m), 4.60 (s), 6.40 (s), 6.43 (s), 6.96-8.05 (overlapping m).

[0748] Biological Activity

[0749] The in vitro activities, against integrase, of compounds of the present invention were measured by one of the following three methods.

[0750] Method A:

[0751] In Method A, the in vitro activity against integrase was measured in a manner which was similar to previously disclosed methods (cf. Hazuda, D. J.; Felock, P.; Witmer, M.; Wolfe, A.; Stillmock, K.; Grobler, J. A.; Espeseth, A.; Gabryelski, L.; Schleif, W.; Blau, C.; Miller, M. D. Science, 2000, 287, 646) Purified recombinant HIV-1 integrase was incubated with immobilized precleaved substrate DNA in a 96 well plate for 20 min at 37° C. After the integration complex was formed, compounds at desired concentrations were added to the wells followed by a 10 min incubation at 37° C. Biotinyted Target DNA was then added and the reaction was carried out for an additional 1 hour at 37° C. Wells were then washed thoroughly to remove any free DNA and integration activity was measured by using a commercial kit to quantitate the amount of biotinyted target DNA integrated into the substrate.

[0752] Method B (SPA Assay):

[0753] In Method B, the in vitro activity against integrase was measured by binding, for each reaction, 5 pmole of biotin labeled substrate DNA to 100 ug of Streptavidin coated PVT SPA beads (Amersham Pharmacia Biotech). 0.26 ng of recombinant integrase was then incubated with the beads for 90 min at 37° C. Unbound enzyme was removed by washing the complex followed by addition of inhibitors and 0.1 fmol of P33 labeled target DNA. Reaction was stopped by adding EDTA to a final concentration of 10 mM. Samples were counted in TopCountNXT (Packard) and the CPM was used as a measure of integration. Reaction condition was as described in A. Engelman and R. Craigie, J. Virol. 69, 5908-5911 (1995). The sequences of substrate and target DNA were described in Nucleic Acid Research 22, 1121-1122 (1994).

[0754] Method C (Electroluminesence Assay):

[0755] The ECL assay of Method C is essentially the same as the SPA assay of Method B, except that 0.5 μg of Streptavidin coated magnetic beads and 0.5 pmol Ru labeled target DNA were used for each reaction instead of SPA beads and P33 labeled DNA. The samples were read in a M8 analyzer (IGEN International, Inc). Percent inhibition of Compound HIV Integrase Number at 70 uM Assay Method 1 40 A 2 88 A 3 99 A 4 90 A 5 65 A 6 75 A 7 32 A 10 79 A 11 97 B 12 85 A 13 94 A 14 94.5 B 15 97 A 16 97 B 17 89.5 A 18 89.5 A 19 96.5 A 20 97.5 A 21 98 A 22 75 A 23 55 A 24 90 A 25 96.5 A 26 97 A 27 33.5 A 28 96.5 A 29 38 A 30 84 A 31 82 A 32 93 A 33 90 A 34 85 A 35 95.5 A 36 30 A 37 82.5 A 38 70 A 39 85 A 40 90 A 41 95 A 42 91 A 43 93.5 A 44 95.5 C 45 99 C 46 99 C 47 99 C 48 99 C 49 99 C 50 99 C 51 100 C 52 99 C 53 99 B 54 99 B 55 99 B 56 88 B 57 99 B 58 99 B 59 98 B 60 99 B 61 99 B 62 99 B 63 98 B 64 95 B 70 92 B 71 99 B 72 99 B 73 99 B 74 98 B 75 91 C 76 99 B 77 60 A 78 75 C 79 90 C 80 90 B 81 95 B 82 80 A 84 88 B 85 94 C 86 97 C 87 99 C 88 90 A 91 99 B 92 94 B 94 55 B 95 45 B 96 65 B 97 70 B 98 80 B 99 80 B 100 70 B 101 80 B 102 60 B 103 80 B 104 83 B 105 35 B 106 40 B 107 80 B 108 65 B 109 60 B 111 25 B 112 99 B 114 97 B 115 97 B 116 100 B 117 68 B 118 85 B 119 40 B 120 97 B 121 95 B 123 98 B 125 75 B 144 83 C 145 95 A 146 98 B 147 98 C 

We claim:
 1. A compound of the formula

wherein: a) R¹ is C₁-C₄ alkyl, carbocyclic radical, heterocyclic radical, aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—, wherein R¹ is optionally substituted from 1-3 tines with halo, C₁-C₂ alkyl or C₁-C₂ alkoxy, or R¹ is H; b) R² is H or C₁-C₄ alkyl; c) R³ is H, C₁-C₄ alkyl or phenyl-C₀-C₂ alkylene which is optionally substituted with 1-3 R⁵; d) R⁴ is carbocylic radical, heterocyclic radical, aryloxy, aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R⁴ is optionally substituted with 1-3 R⁵, provided that, when R¹, R² and R³ are each H, R4 is not unsubstituted phenyl, o-methoxyphenyl or naphthalen-1-yl; e) each R⁵ is independently selected from H, halo, C₁-C₄ alkyl, C₁-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl, R⁶-phenoxy, R⁶-benzyl, R⁶-benzyloxy, NH₂C(O)—, alkyl-NHC(O)—; f) R⁶ is H, halo; g) Z is a bond or a substituted or unsubstituted C₁-C₄ alkylene group; h) B¹ is selected from the group consisting of

i) R⁷ is H or C₁-C₄ alkyl, or a pharmaceutically acceptable salt or solvate thereof.
 2. A compound of the formula

wherein: a) R¹ is C₁-C₄ alkyl, carbocyclic radical, heterocyclic radical, aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—, wherein R¹ is optionally substituted from 1-3 times with halo, C₁-C₂ alkyl or C₁-C₂ alkoxy, or R¹ is H; b) R² is H or C₁-C₄ alkyl; c) R³ is H, C₁-C₄ alkyl or phenyl-C₀-C₂ alkylene which is optionally substituted with 1-3 R⁵; d) R⁴ is carbocylic radical, heterocyclic radical, aryloxy, aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R⁴ is optionally substituted with 1-3 R⁵, provided that, when R¹, R² and R³ are each H, R4 is not unsubstituted phenyl, o-methoxyphenyl or naphthalen-1-yl; e) each R⁵ is independently selected from H, halo, C₁-C₄ alkyl, C₁-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl, R⁶-phenoxy, R⁶-benzyl, R⁶-benzyloxy, NH₂C(O)—, alkyl-NHC(O)—; f) R⁶ is H, halo; g) Z is a bond or a substituted or unsubstituted C₁-C₄ alkylene group; h) B¹ is selected from the group consisting of

i) R⁷ is H or C₁-C₄ alkyl, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 3. A prodrug of claim 2 having the formula

wherein: a) R1 is C₁-C₄ alkyl, carbocyclic radical, heterocyclic radical, aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—, wherein R¹ is optionally substituted from 1-3 times with halo, C₁-C₂ alkyl or C₁-C₂ alkoxy, or R¹ is H; b) R² is H or C₁-C₄ alkyl; c) R³ is H, C₁-C₄ alkyl or phenyl-C₀-C₂ alkylene which is optionally substituted with 1-3 R⁵; d) R⁴ is carbocylic radical, heterocyclic radical, aryloxy, aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R⁴ is optionally substituted with 1-3 R⁵, provided that, when R¹, R² and R³ are each H, R4 is not unsubstituted phenyl, o-methoxyphenyl or naphthalen-1-yl; e) each R⁵ is independently selected from H, halo, C₁-C₄ alkyl, C₁-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl, R⁶-phenoxy, R⁶-benzyl, R⁶-benzyloxy, NH₂C(O)—, alkyl-NHC(O)—; f) R⁶ is H, halo; and g) Z is a bond or a substituted or unsubstituted C₁-C₄ alkylene group.
 4. A compound of the formula

wherein: a) W¹ is a bond or a C₁-C₄ alkylene group; b) R¹¹ is aryl, aryloxy, aryl-cyclopropylene, heteroaryl, heteroaryloxy, wherein R¹¹ is optionally substituted from 1-3 times with halo, C₁-C₂ alkyl or C₁-C₂ alkoxy, or wherein R¹¹ is H; c) Y¹ is a bond, C₁-C₃ alkylene or —O—C₁-C₂ alkylene; d) each R¹³ is independently selected from H, halo, N₂O, C₁-C₄ alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkyl, phenyl, phenoxy, benzyl, benzyloxy, p-halophenyl, p-halobenzyl, p-halophenoxy and p-halobenzyloxy; and e) B² is selected from

or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 5. A compound of the formula

wherein: a) W¹ is C₁-C₃ alkylene; b) R¹¹ is aryl, aryloxy, aryl-cyclopropylene, heteroaryl, heteroaryloxy, wherein R¹¹ is optionally substituted from 1-3 times with halo, C₁-C₂ alkyl or C₁-C₂ alkoxy, or R¹¹ is H; c) y² is a bond, C₁-C₃ alkylene; d) each R¹⁴ is independently selected from H, halo, C₁-C₂ alkyl C₁-C₂ alkoxy, C₁-C₂ haloalkyl; and e) B² is selected from

or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 6. A compound of the formula

wherein: a) independently, each Q is a bond or a methylene group; b) each R¹⁵ is independently selected from H, halo, N₂O, C₁-C₄ alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkyl and CONHCH₃; R¹⁶ is H or C₁-C₂ alkyl; and c) B² is selected from

or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 7. A compound of the formula

wherein: a) R¹ is C₁-C₄ alkyl, carbocyclic radical, heterocyclic radical, aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—, wherein R¹ is optionally substituted from 1-3 times with halo, C₁-C₂ alkyl or C₁-C₂ alkoxy, or R¹ is H; b) R² is H or C₁-C₄ alkyl; c) R³ is H, C₁-C₄ alkyl or phenyl-C₀-C₂ alkylene which is optionally substituted with 1-3 R⁵; d) R^(4a) is carbocylic radical, heterocyclic radical, aryloxy, aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R4a is optionally substituted with 1-3 R⁵ e) each R⁵ is independently selected from H, halo, C₁-C₄ alkyl, C₁-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl, R⁶-phenoxy, R⁶-benzyl, R⁶-benzyloxy, NH₂C(O)—, alkyl-NHC(O)—; f) R⁶ is H, halo; and g) z is a bond or a substituted or unsubstituted C₁-C₄ alkylene group.
 8. A pharmaceutical composition, comprising a) a compound of the formula

 wherein: (i) R¹ is C₁-C₄ alkyl, carbocyclic radical, heterocyclic radical, aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—, wherein R¹ is optionally substituted from 1-3 times with halo, C₁-C₂ alkyl or C₁-C₂ alkoxy, or R¹ is H; (ii) R is H or C₁-C₄ alkyl; (iii) R³ is H, C₁-C₄ alkyl or phenyl-C₀-C₂ alkylene which is optionally substituted with 1-3 R⁵; (iv) R^(4a) is carbocylic radical, heterocyclic radical, aryloxy, aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R^(4a) is optionally substituted with 1-3 R⁵; (v) each R⁵ is independently selected from H, halo, C₁-C₄ alkyl, C₁-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl, R⁶-phenoxy, R⁶-benzyl, R⁶-benzyloxy, NH₂C(O)—, alkyl-NHC(O)—; (vi) R⁶ is H, halo; (vii) Z is a bond or a substituted or unsubstituted C₁-C₄ alkylene group; (viii) and B² is selected from

 or a pharmaceutically acceptable salt, solvate or prodrug thereof; and b) a pharmaceutically acceptable carrier.
 9. The pharmaceutical composition of claim 8, further comprising a therapeutically effective amount of one or more other HIV treatment agents selected from (a) an HIV protease inhibitor, (b) a nucleoside reverse transcriptase inhibitor, (c) a non-nucleoside reverse transcriptase inhibitor, (d) an HIV-entry inhibitor, or (e) an immunomodulator, or a combination thereof.
 10. A method of inhibiting HIV integrase which comprises administering to a mammal in need of such treatment a therapeutically effective amount a compound of the formula

wherein: a) R1 is C₁-C₄ alkyl, carbocyclic radical, heterocyclic radical, aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—, wherein R¹ is optionally substituted from 1-3 times with halo, C₁-C₂ alkyl or C₁-C₂ alkoxy, or R¹ is H; b) R² is H or C₁-C₄ alkyl; c) R³ is H, C₁-C₄ alkyl or phenyl-C₀-C₂ alkylene which is optionally substituted with 1-3 R⁵; d) R^(4a) is carbocylic radical, heterocyclic radical, aryloxy, aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R^(4a) is optionally substituted with 1-3 R⁵; e) each R⁵ is independently selected from H, halo, C₁-C₄ alkyl, C₁-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl, R⁶-phenoxy, R⁶-benzyl, R⁶-benzyloxy, NH₂C(O)—, alkyl-NHC(O)—; f) R⁶ is H, halo; g) Z is a bond or a substituted or unsubstituted C₁-C₄ alkylene group; and h) B² is selected from

 or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 11. A method of for treating an HIV infection, in a patient in need thereof, comprising the administration to said patient of a therapeutically effective amount a compound of the formula

wherein: a) R1 is C₁-C₄ alkyl, carbocyclic radical, heterocyclic radical, aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—, wherein R¹ is optionally substituted from 1-3 times with halo, C₁-C₂ alkyl or C₁-C₂ alkoxy, or R¹ is H; b) R² is H or C₁-C₄ alkyl; c) R³ is H, C₁-C₄ alkyl or phenyl-C₀-C₂ alkylene which is optionally substituted with 1-3 R⁵; d) R^(4a) is carbocylic radical, heterocyclic radical, aryloxy, aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R^(4a) is optionally substituted with 1-3 R⁵; e) each R⁵ is independently selected from H, halo, C₁-C₄ alkyl, C₁-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl, R⁶-phenoxy, R⁶-benzyl, R⁶-benzyloxy, NH₂C(O)—, alkyl-NHC(O)—; f) R⁶ is H, halo; g) Z is a bond or a substituted or unsubstituted C₁-C₄ alkylene group; and h) B² is selected from

 or a pharmaceutically acceptable salt, solvate or prodrug thereof.
 12. A method of prophylactically or therapeutically treating AIDS or ARC, in a patient in need thereof, comprising the administration to said patient of a therapeutically effective amount a compound of the formula

wherein: a) R¹ is C₁-C₄ alkyl, carbocyclic radical, heterocyclic radical, aryl-C₁-C₂ alkylene, aryloxy-C₁-C₂ alkylene, alkoxy-CC(O)—, wherein R¹ is optionally substituted from 1-3 times with halo, C₁-C₂ alkyl or C₁-C₂ alkoxy, or R¹ is H; b) R² is H or C₁-C₄ alkyl; c) R³ is H, C₁-C₄ alkyl or phenyl-C₀C₂ alkylene which is optionally substituted with 1-3 R⁵; d) R^(4a) is carbocylic radical, heterocyclic radical, aryloxy, aryl-C₁-C₄ alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R^(4a) is optionally substituted with 1-3 R⁵; e) each R⁵ is independently selected from H, halo, C₁-C₄ alkyl, C₁-C₄ alkenyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, R⁶-phenyl, R⁶-phenoxy, R⁶-benzyl, R⁶-benzyloxy, NH₂C(O)—, alkyl-NHC(O)—; f) R⁶ is H, halo; g) A is a bond or a substituted or unsubstituted C₁-C₄ alkylene group; and h) B² is selected from 